Posts Tagged ‘Johns Hopkins University’

Fighting Chaos with care, community trust, engagement must be cornerstones of pandemic response

Reporter: Amandeep Kaur, BSc, MSc (Exp. 6/2021)

According to the Global Health Security Index released by Johns Hopkins University in October 2019 in collaboration with Nuclear Threat Initiative (NTI) and The Economist Intelligence Unit (EIU), the United States was announced to be the best developed country in the world to tackle any pandemic or health emergency in future.

The table turned within in one year of outbreak of the novel coronavirus COVID-19. By the end of March 2021, the country with highest COVID-19 cases and deaths in the world was United States. According to the latest numbers provided by World Health Organization (WHO), there were more than 540,000 deaths and more than 30 million confirmed cases in the United States.

Joia Mukherjee, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School said,

“When we think about how to balance control of an epidemic over chaos, we have to double down on care and concern for the people and communities who are hardest hit”.

She also added that U.S. possess all the necessary building blocks required for a health system to work, but it lacks trust, leadership, engagement and care to assemble it into a working system.

Mukherjee mentioned about the issues with the Index that it undervalued the organized and integrated system which is necessary to help public meet their needs for clinical care. Another necessary element for real health safety which was underestimated was conveying clear message and social support to make effective and sustainable efforts for preventive public health measures.

Mukherjee is a chief medical officer at Partners In Health, an organization focused on strengthening community-based health care delivery. She is also a core member of HMS community members who play important role in constructing a more comprehensive response to the pandemic in all over the U.S. With years of experience, they are training global health care workers, analyzing the results and constructing an integrated health system to fight against the widespread health emergency caused by coronavirus all around the world.

Mukherjee encouraged to strengthen the consensus among the community to constrain this infectious disease epidemic. She suggested that validation of the following steps are crucial such as testing of the people with symptoms of infection with coronavirus, isolation of infected individuals by providing them with necessary resources and providing clinical treatment and care to those people who are in need. Mukherjee said, that community engagement and material support are not just idealistic goal rather these are essential components for functioning of health care system during an outburst of coronavirus.

Continued alertness such as social distancing and personal contact with infected individual is important because it is not possible to rapidly replace the old-school public health approaches with new advanced technologies like smart phone applications or biomedical improvements.

Public health specialists emphasized that the infection limitation is the only and most vital strategy for controlling the outbreak in near future, even if the population is getting vaccinated. It is crucial to slowdown the spread of disease for restricting the natural modification of more dangerous variants as that could potentially escape the immune protection mechanism developed by recently generated vaccines as well as natural immune defense systems.

Making Crucial connections

The treatment is more expensive and complicated in areas with less health facilities, said Paul Farmer, the Kolokotrones University Professor at Harvard and chair of the HMS Department of Global Health and Social Medicine. He called this situation as treatment nihilism. Due to shortage of resources, the maximum energy is focused in public health care and prevention efforts. U.S. has resources to cope up with the increasing demand of hospital space and is developing vaccines, but there is a form of containment nihilism- which means prevention and infection containment are unattainable- said by many experts.

Farmer said, integration of necessary elements such as clinical care, therapies, vaccines, preventive measures and social support into a single comprehensive plan is the best approach for a better response to COVID-19 disease. He understands the importance of community trust and integrated health care system for fighting against this pandemic, as being one of the founders of Partners In Health and have years of experience along with his colleagues from HMS and PIH in fighting epidemics of HIV, Ebola, cholera, tuberculosis, other infectious and non-infectious diseases.

PIH launched the Massachusetts Community Tracing Collaborative (CTC), which is an initiative of contact tracing statewide in partnership with several other state bodies, local boards of Health system and PIH. The CTC was setup in April 2020 in U.S. by Governor Charlie Baker, with leadership from HMS faculty, to build a unified response to COVID-19 and create a foundation for a long-term movement towards a more integrated community-based health care system.

The contact tracing involves reaching out to individuals who are COVID-19 positive, then further detect people who came in close contact with infected individuals and screen out people with coronavirus symptoms and encourage them to seek testing and take necessary precautions to break the chain of infection into the community.

In the initial phase of outbreak, the CTC group comprises of contact tracers and health care coordinators who spoke 23 different languages, including social workers, public health practitioners, nurses and staff members from local board health agencies with deep links to the communities they are helping. The CTC worked with 339 out of 351 state municipalities with local public health agencies relied completely on CTC whereas some cities and towns depend occasionally on CTC backup. According to a report, CTC members reached up to 80 percent of contact tracking in hard-hit and resource deprived communities such as New Bedford.

Putting COVID-19 in context

Based on generations of experience helping people surviving some of the deadliest epidemic and endemic outbreaks in places like Haiti, Mexico, Rwanda and Peru, the staff was alert that people with bad social and economic condition have less space to get quarantined and follow other public health safety measures and are most vulnerable people at high risk in the pandemic situation.

Infected individuals or individuals at risk of getting infected by SARS-CoV-2 had many questions regarding when to seek doctor’s help and where to get tested, reported by contact tracers. People were worried about being evicted from work for two weeks and some immigrants worried about basic supplies as they were away from their family and friends.

The CTC team received more than 7,000 requests for social support assistance in the initial three months. The staff members and contact tracers were actively connecting the resourceful individuals with the needy people and filling up the gap when there was shortage in their own resources.

Farmer said, “COVID is a misery-seeking missile that has targeted the most vulnerable.”

The reality that infected individuals concerned about lacking primary household items, food items and access to childcare, emphasizes the urgency of rudimentary social care and community support in fighting against the pandemic. Farmer said, to break the chain of infection and resume society it is mandatory to meet all the elementary needs of people.

“What kinds of help are people asking for?” Farmer said and added “it’s important to listen to what your patients are telling you.”

An outbreak of care

The launch of Massachusetts CTC with the support from PIH, started receiving requests from all around the country to assist initiating contact tracing procedures. In May, 2020 the organization announced the launch of a U.S. public health accompaniment to cope up with the asked need.

The unit has included team members in nearly 24 states and municipal health departments in the country and work in collaboration with local organizations. The technical support on things like choosing and implementing the tools and software for contact tracing was provided by PIH. To create awareness and provide new understanding more rapidly, a learning collaboration was established with more than 200 team members from more than 100 different organizations. The team worked to meet the needs of population at higher risk of infection by advocating them for a stronger and more reliable public health response.

The PIH public health team helped to train contact trackers in the Navajo nation and operate to strengthen the coordination between SARS-CoV-2 testing, efforts for precaution, clinical health care delivery and social support in vulnerable communities around the U.S.

“For us to reopen our schools, our churches, our workplaces,” Mukherjee said, “we have to know where the virus is spreading so that we don’t just continue on this path.”



Other related articles were published in this Open Access Online Scientific Journal, including the following:

T cells recognize recent SARS-CoV-2 variants

Reporter: Aviva Lev-Ari, PhD, RN


The WHO team is expected to soon publish a 300-page final report on its investigation, after scrapping plans for an interim report on the origins of SARS-CoV-2 — the new coronavirus responsible for killing 2.7 million people globally

Reporter: Aviva Lev-Ari, PhD, RN


Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN


Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD


Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2

Reporter: Irina Robu, PhD


Read Full Post »

North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis

Reporter: Aviva Lev-Ari, PhD, RN

Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis in North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

A. Dénise den Haan, MD, Boon Yew Tan, MBChB, Michelle N. Zikusoka, MD, Laura Ibañez Lladó, MS, Rahul Jain, MD, Amy Daly, MS, Crystal Tichnell, MGC, Cynthia James, PhD, Nuria Amat-Alarcon, MS, Theodore Abraham, MD, Stuart D. Russell, MD,David A. Bluemke, MD, PhD, Hugh Calkins, MD, Darshan Dalal, MD, PhD and Daniel P. Judge, MD

Author Affiliations

From the Department of Medicine/Cardiology (A.D.d.H., B.Y.T., M.N.Z., L.I.L., R.J., A.D., C.T., C.J., N.A.-A., T.A., S.D.R., H.C., D.D., D.P.J.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Cardiology, Division of Heart and Lungs (A.D.d.H.), University Medical Center Utrecht, Utrecht, The Netherlands; and National Institutes of Health, Radiology and Imaging Sciences (D.A.B.), Bethesda, Md.

Correspondence to Daniel P. Judge, MD, Johns Hopkins University, Division of Cardiology, Ross 1049; 720 Rutland Avenue, Baltimore, MD 21205. E-mail djudge@jhmi.edu


Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C.

Methods and Results— In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation.

Conclusions— Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.


Circulation: Cardiovascular Genetics.2009; 2: 428-435

Published online before print June 3, 2009,

doi: 10.1161/ CIRCGENETICS.109.858217


Read Full Post »

Healthcare Startups Accelerator is Reaching Out: Deadline November 11, 2013

Reporter: Aviva Lev-Ari, PhD, RN

Applications for companies are due November 11, 2013.

We are also seeking exceptional individuals looking to join a team, particularly those with software development or data science skills. Individuals interested in working with one of the startups can also apply to the program and applications for individuals are due December 16, 2013. Individuals will be matched with companies throughout January.

DreamIt Health Baltimore 2014

baltimorebrought to you byAPPLY TODAY

Applications are due November 11, 2013

Apply as a company | Apply as an individual

Follow us on Twitter | DreamIt Ventures on Facebook

DreamIt Health Baltimore is designed to speed the growth and success of early-stage health IT companies through its program in Central Maryland. Powered by the Johns Hopkins UniversityBioHealth Innovation, and DreamIt Ventures – the program gives participants access and advantages typically out-of-reach to healthcare startups.

DreamIt works with extraordinary teams to create exceptional companies, accomplishing in 3-6 months what would otherwise take years. DreamIt accelerators are characterized by seed capital, intense 1-on-1 mentorship from dedicated, previously successful tech entrepreneurs, access to key people, expertise, and information typically beyond the reach of a startup, informal education from leading industry practitioners, a robust network of DreamIt alumni, and a wide range of free services.  Following a lean startup methodology, the selected teams focus on rapid, iterative interactions with their target markets to reduce risk and find product-market fit as quickly as possible.

DreamIt Health Baltimore 2014 will select up to ten companies from around the world to participate in a four-month accelerator program. In addition to receiving up to a $50,000 stipend and professional services, the startups will be paired with and work closely with exited entrepreneurs-turned-mentors with domain expertise specific to their needs; benefit from an intense startup and healthcare curriculum taught by accomplished practitioners; meet with subject matter experts and investors; and enjoy access to executives, information systems, and data from leading industry players including providers, payers, biopharma, device makers, and federal agencies. Participating teams will also benefit from DreamIt’s extensive network and expertise in guiding the growth of young technology companies.

DreamIt Health Baltimore is expected to take advantage of many of the strengths of the region, giving participating startups the opportunity to work closely with Johns Hopkins Medicine for potential pilots and also access to key individuals throughout the region’s wealth of federal health care institutions including the Center for Medicare and Medicaid Services, the Food and Drug Administration, the National Institutes of Health and the Agency for Healthcare Research and Quality.

The program will be led by Elliot Menschik, MD PhD, a Johns Hopkins alum and successfully-exited health IT entrepreneur.

Learn more about DreamIt Health Baltimore…
Apply to DreamIt Health Baltimore
Apply as an individual
Questions? Ask us.

Press Highlights DreamIt Health Philadelphia (Held April 8th 2013-August 8th 2013)
DreamIt Ventures Teams Up with Blue Cross, Penn Medicine to Launch and Accelerator for Health Startups

Improving outcomes, speeding up diagnoses among goals of Dreamit Venture’s first health IT accelerator

New incubator DreamIt Health launches first class

Next Big Thing In Health Care May Come From Philly Business Incubator

DreamIt ‘boot camp’ boosts health-care info start-ups

DreamIt Health startup accelerator are recruiting ten healthtech startups

Founder at UACTIFY

DreamIt Health startup accelerator is reaching out in the hopes that you might be open to getting the word out among Health 2.0 Israel members about the upcoming DreamIt Health startup accelerator in partnership with Johns Hopkins.

DreamIt Health startup accelerator are recruiting for (and applications are open for) up to ten healthtech startups from around the world to come to Baltimore for a four-month program to achieve significant business milestones in delivering products that solve real problems for key healthcare stakeholders. DreamIt Health startup accelerator do this by removing as many obstacles as possible from the team’s path and providing guidance and access to people and resources otherwise out of their reach. The capstone of the program, Demo Day, gives these teams the opportunity to unveil their products and progress before a few hundred early stage investors and key industry figures.

In addition to receiving up to a $50,000 stipend, free workspace and top-shelf legal services, the startups will be paired 1-on-1 with previously successful entrepreneurs customized to the needs of each team. These mentors will contribute considerable time and effort to guide and assist the founders. Participants will also benefit from an intense startup and healthcare curriculum taught by accomplished practitioners, meet regularly with subject matter experts and investors, and enjoy access to executives, systems, and data from leading industry players including providers, payers, biopharma, device makers, and federal agencies. Participating teams will also benefit from DreamIt’s extensive network and expertise in guiding the growth of young technology companies.

DreamIt Health startup accelerator were founded in 2008 and are run by a group of successful tech entrepreneurs. To date, DreamIt has worked closely with 127 companies from around the world through accelerators in Philadelphia, New York, Austin, and Tel Aviv. These programs are characterized by seed capital, intense 1-on-1 mentorship from dedicated, previously successful tech entrepreneurs, access to key people, expertise, and information typically beyond the reach of a startup, informal education from leading industry practitioners, a robust network of DreamIt alumni, and a wide range of free services. Following a lean startup methodology, the selected teams focus on rapid, iterative interactions with their target markets to reduce risk and find product-market fit as quickly as possible. Forbes has named DreamIt among the top three accelerators in the world and DreamIt companies have gone on to raise nearly $100M in follow-on capital with an aggregate value north of $400M.

DreamIt Health startup accelerator are looking for extraordinary people and teams developing IT-based products with the potential to solve significant problems faced by key stakeholders in the industry including providers, payers, public health, biopharma, device makers, employers and patients themselves. Interested teams can apply at http://www.dreamithealth.com. Applications for companies are due November 11, 2013. We are also seeking exceptional individuals looking to join a team, particularly those with software development or data science skills. Individuals interested in working with one of the startups can also apply to the program and applications for individuals are due December 16, 2013. Individuals will be matched with companies throughout January.

Read Full Post »

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Curator: Aviva Lev-Ari, PhD, RN

This image has an empty alt attribute; its file name is ArticleID-73.png

WordCloud Image Produced by Adam Tubman

Article VI Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart

Image created by Adina Hazan 06/30/2021

This article is Part VI in a Series of articles on Calcium Release Mechanism, the series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP


Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN


Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN


Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN


Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN


Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part IXCalcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP


Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


This article has THREE parts:

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

The following two discoveries in Cardiac Gene Therapies represent the FRONTIER IN CARDIOLOGY for 2012 – 2013: Solution Advancement for Improving Myocardial Contractility

Part I: Scientific Leader in Cardiology, Contributions by Roger J. Hajjar, MD to Gene Therapy

Roger J. Hajjar, MD, a pioneering Mount Sinai researcher who has published cutting-edge studies on heart failure, has been named the recipient of the 2013 BCVS Distinguished Achievement Award by theAmerican Heart Association and the Council on Basic Cardiovascular Sciences. Dr. Hajjar, who is The Arthur and Janet C. Ross Professor of Medicine and Director of The Helmsley Trust Translational Research Center, will be honored at the American Heart Association’s Scientific Sessions Annual Conference later this year.

“Dr. Hajjar will receive the award for his groundbreaking contributions to developing gene therapy treatments for cardiac disease,” says Joshua Hare, MD, who is President-elect of the Council on Basic Cardiovascular Sciences. He will also be recognized for his work on behalf of the Council.

Over the years, Dr. Hajjar’s laboratory has made important basic science discoveries that were translated into clinical trials. Most recently, Dr. Hajjar and his researchers identified a possible new drug target for treating or preventing heart failure. Says Mark A. Sussman, PhD, a former president of the Council, “Dr. Hajjar was among the first, and certainly the most successful, in combining gene therapy and treatment of heart failure. He shows a relentless pursuit of translating basic science into real-world treatment of heart disease.”

This article was first published in Inside Mount Sinai.


John Hopkins, Distinguished Alumnus Award 2011

Roger J. Hajjar, Engr ’86
Dr. Roger Hajjar received his bachelor’s degree in biomedical engineering from Johns Hopkins University in 1986. A cardiologist and translational scientist, he is a leader in gene therapy techniques and model testing for cardiovascular diseases. Dr. Hajjar is professor of medicine and cardiology, and professor of gene and cell medicine at Mount Sinai Medical Center in New York, as well as research director of Mount Sinai’s Wiener Family Cardiovascular Research Laboratories. Dr. Hajjar was recruited to Mt. Sinai from Harvard Medical School where he was assistant professor of medicine and staff cardiologist in the Heart Failure & Cardiac Transplantation Center. He received his medical degree from Harvard Medical School and trained in internal medicine and cardiology at Massachusetts General Hospital in Boston. Dr. Hajjar has concentrated his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques in the heart to improve contractility. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis. Dr. Hajjar has significant expertise in gene therapy. In 1996, he won the Young Investigator Award of the American Heart Association (Council on Circulation). In 1999, Dr. Hajjar was awarded the prestigious Doris Duke Clinical Scientist award and won first prize at the Astra Zeneca Young Investigator Forum. Dr. Hajjar holds a number of NIH grants.


Dr Hajjar is the Director of the Cardiovascular Research Center, and the Arthur & Janet C. Ross Professor of Medicine at Mount Sinai School of Medicine, New York, NY. He received his BS in Biomedical Engineering from Johns Hopkins University and his MD from Harvard Medical School and the Harvard-MIT Division of Health Sciences & Technology. He completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Dr. Hajjar is an internationally renowned scientific leader in the field of cardiac gene therapy for heart failure. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models. The significance of Dr Hajjar’s research has been recognized with the initiation and recent successful completion of phase 1 and phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure under his guidance.

Prior to joining Mount Sinai, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital.

Dr. Hajjar has won numerous awards and distinctions, including the Young Investigator Award of the American Heart Association. He was awarded a Doris Duke Clinical Scientist award and has won first prize at the Astra Zeneca Young Investigator Forum. He is a member of the American Society for Clinical Investigation. He was recently awarded the Distinguished Alumnus Award from Johns Hopkins University and the Mount Sinai Dean’s award for Excellence in Translational Science. He has authored over 260 peer-reviewed publications.


Meet the Director of Mount Sinai’s Cardiovascular Research Center

“Cardiovascular diseases are the number one cause of death globally. In order to tackle them in all aspects, we must unite improved diagnostic techniques with more refined therapies.”

Roger J. Hajjar, MD, Director of the Cardiovascular Research Center, the Arthur & Janet C. Ross Professor of Medicine, Professor of Gene & Cell Medicine, Director of the Cardiology Fellowship Program, and Co-Director of the Transatlantic Cardiovascular Research Center, which combines Mount Sinai Cardiology Laboratories with those of the Universite de Paris – Madame Curie.

In the late 1990s, the possibility that discoveries in genetics and genomics could have a positive impact on the diagnosis, treatment, and prevention of cardiovascular diseases seemed to be just a distant promise. Today, a little more than a decade later, the promise is beginning to take shape. Roger J. Hajjar, MD and his multidisciplinary team of investigators are beginning to translate scientific findings into real therapies for cardiovascular diseases. As Director of the Cardiovascular Research Institute and a cardiologist by training, Dr. Hajjar guides the growth of a cutting-edge translational research laboratory, which is positioning Mount Sinai as the leader in cardiovascular genomics.

An internationally recognized scientific leader in the field of cardiac gene therapy for heart failure, Dr. Hajjar is expanding studies of the basic mechanisms of cardiac diseases and identification of high-risk groups and genomic predictors so that they can be part of the daily clinical care of patients. Unique biorepositories combined with cardiovascular areas of excellence across Mount Sinai make possible crucial genetic studies.

First Gene Therapy for Heart Failure

Under Dr. Hajjar’s leadership, the Cardiovascular Research Center has already developed the world’s first potential gene therapy for heart failure. Known as AAV1.SERCA2a, this therapy actually revives heart tissue that has stopped working properly. It has led to new treatment possibilities for patients with advanced heart failure, whose options used to be severely limited. The significance of this research has been recognized with the initiation and successful completion Phase 1 and Phase 2 First-in-Man clinical trials of SERCA2a gene transfer in patients with advanced heart failure. Phase 3 validation begins in 2011.

The Cardiovascular Research Center’s next research projects, already underway, focus on using novel gene therapy vectors to target diastolic heart failure, ventricular arrhythmias, pulmonary hypertension, and myocardial infarctions.

In addition to targeting signaling pathways to aid failing heart cells, ongoing work at the Cardiovascular Research Center involves studying how to block signaling pathways in cardiac hypertrophy as well as apoptosis. The laboratory team is also targeting a number of signaling pathways in the aging heart to improve dystolic function.

Prior to joining Mount Sinai in 2007, Dr. Hajjar served as Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has also been a staff cardiologist in the Heart Failure & Cardiac Transplantation Center at Massachusetts General Hospital. After earning a bachelors of science degree in Biomedical Engineering from Johns Hopkins University and a medical degree from Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology, he completed his training in internal medicine, cardiology and research fellowships at Massachusetts General Hospital in Boston.

Scientific Advisors

Roger J. Hajjar, MD, Co-Founder and a Scientific Advisor of Celladon Co, plans to commercialize AAV1.SERCA2a for the treatment of heart failure.
Dr. Roger J. Hajjar is the Director of the Cardiovascular Research Center at the Mt. Sinai School of Medicine. Previously, he was the Director of the Cardiovascular Laboratory of Integrative Physiology and Imaging at Massachusetts General Hospital (MGH) and Associate Professor of Medicine at Harvard Medical School. Dr. Hajjar has an active basic science laboratory and concentrates his research efforts on understanding the basic mechanisms of heart failure. He has developed gene transfer methods and techniques targeting the heart as a therapeutic modality to improve contractility in heart failure. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis.

Gene Therapy: Volume 19, Issue 6 (June 2012)

Special Issue: Cardiovascular Gene Therapy

Guest Editor

Roger J Hajjar MD, Mount Sinai School of Medicine, New York, NY Director, Cardiovascular Research Institute, Arthur & Janet C Ross Professor of Medicine

SDF-1 in myocardial repair  

M S Penn, J Pastore, T Miller and R Aras

Gene Ther 19: 583-587; doi:10.1038/gt.2012.32

Abstract | Full Text | PDF

Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?  

R A Li

Gene Ther 19: 588-595; doi:10.1038/gt.2012.33

Abstract | Full Text | PDF

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy  

J-S Hulot, G Senyei and R J Hajjar

Gene Ther 19: 596-599; advance online publication, May 17, 2012; doi:10.1038/gt.2012.34

Abstract | Full Text | PDF

Gene therapy for ventricular tachyarrhythmias  

J K Donahue

Gene Ther 19: 600-605; advance online publication, April 26, 2012; doi:10.1038/gt.2012.35

Abstract | Full Text | PDF

Prospects for gene transfer for clinical heart failure  

T Tang, M H Gao and H Kirk Hammond

Gene Ther 19: 606-612; advance online publication, April 26, 2012; doi:10.1038/gt.2012.36

Abstract | Full Text | PDF

Targeting S100A1 in heart failure  

J Ritterhoff and P Most

Gene Ther 19: 613-621; advance online publication, February 16, 2012; doi:10.1038/gt.2012.8

Abstract | Full Text | PDF

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond  

M Giacca and S Zacchigna

Gene Ther 19: 622-629; advance online publication, March 1, 2012; doi:10.1038/gt.2012.17

Abstract | Full Text | PDF

Vein graft failure: current clinical practice and potential for gene therapeutics  

S Wan, S J George, C Berry and A H Baker

Gene Ther 19: 630-636; advance online publication, March 29, 2012; doi:10.1038/gt.2012.29

Abstract | Full Text | PDF

Percutaneous methods of vector delivery in preclinical models  

D Ladage, K Ishikawa, L Tilemann, J Müller-Ehmsen and Y Kawase

Gene Ther 19: 637-641; advance online publication, March 15, 2012; doi:10.1038/gt.2012.14

Abstract | Full Text | PDF

Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function  

E Di Pasquale, M V G Latronico, G S Jotti and G Condorelli

Gene Ther 19: 642-648; advance online publication, March 1, 2012; doi:10.1038/gt.2012.19

Abstract | Full Text | PDF

Intracellular transport of recombinant adeno-associated virus vectors  

M Nonnenmacher and T Weber

Gene Ther 19: 649-658; advance online publication, February 23, 2012; doi:10.1038/gt.2012.6

Abstract | Full Text | PDF

Gene delivery technologies for cardiac applications  

M G Katz, A S Fargnoli, L A Pritchette and C R Bridges

Gene Ther 19: 659-669; advance online publication, March 15, 2012; doi:10.1038/gt.2012.11

Abstract | Full Text | PDF

Cardiac gene therapy in large animals: bridge from bench to bedside  

K Ishikawa, L Tilemann, D Ladage, J Aguero, L Leonardson, K Fish and Y Kawase

Gene Ther 19: 670-677; advance online publication, February 2, 2012; doi:10.1038/gt.2012.3

Abstract | Full Text | PDF

Progress in gene therapy of dystrophic heart disease  

Y Lai and D Duan

Gene Ther 19: 678-685; advance online publication, February 9, 2012; doi:10.1038/gt.2012.10

Abstract | Full Text | PDF

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade  

J Reinkober, H Tscheschner, S T Pleger, P Most, H A Katus, W J Koch and P W J Raake

Gene Ther 19: 686-693; advance online publication, February 16, 2012; doi:10.1038/gt.2012.9

Abstract | Full Text | PDF

Directed evolution of novel adeno-associated viruses for therapeutic gene delivery  

M A Bartel, J R Weinstein and D V Schaffer

Gene Ther 19: 694-700; advance online publication, March 8, 2012; doi:10.1038/gt.2012.20

Abstract | Full Text | PDF


Part II: Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension

Public release date: 30-Jul-2013

Contact: Lauren Woods
The Mount Sinai Hospital / Mount Sinai School of Medicine

Inhalable gene therapy may help pulmonary arterial hypertension patients

Gene therapy when inhaled may restore function of a crucial enzyme in the lungs to reverse deadly PAH

The deadly condition known as pulmonary arterial hypertension (PAH), which afflicts up to 150,000 Americans each year, may be reversible by using an inhalable gene therapy, report an international team of researchers led by investigators at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

In their new study, reported in the July 30 issue of the journal Circulation, scientists demonstrated that gene therapy administered through a nebulizer-like inhalation device can completely reverse PAH in rat models of the disease. In the lab, researchers also showed in pulmonary artery PAH patient tissue samples reduced expression of the SERCA2a, an enzyme critical for proper pumping of calcium in calcium compartments within the cells. SERCA2a gene therapy could be sought as a promising therapeutic intervention in PAH.

“The gene therapy could be delivered very easily to patients through simple inhalation — just like the way nebulizers work to treat asthma,” says study co-senior investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine and Professor of Gene & Cell at Icahn School of Medicine at Mount Sinai. “We are excited about testing this therapy in PAH patients who are in critical need of intervention.”

This same SERCA2a dysfunction also occurs in heart failure. This new study utilizes the same gene therapy currently being tested in patients to reverse congestive heart failure in a large phase III clinical trial in the United States and Europe.

“What we have shown is that gene therapy restores function of this crucial enzyme in diseased lungs,” says Dr. Hajjar. “We are delighted with these new findings because it suggests that a gene therapy that is already showing great benefit in congestive heart failure patients may be able to help PAH patients who currently have no good treatment options — and are in critical need of a life sustaining therapy.”

When SERCA2a is down-regulated, calcium stays longer in the cells than it should, and it induces pathways that lead to overgrowth of new and enlarged cells. According to researchers, the delivery of the SERCA2a gene produces SERCA2a enzymes, which helps both heart and lung cells restore their proper use of calcium.

“We are now on a path toward PAH patient clinical trials in the near future,” says Dr. Hajjar, who developed the gene therapy approach. Studies in large animal models are now underway. SERCA2a gene therapy has already been approved by the National Institutes of Health for human study.

A Simple Inhalation Corrects Deadly Dysfunction

PAH most commonly results from heart failure in the left side of the heart or from a pulmonary embolism, when clots in the legs travel to the lungs and cause blockages. When the lung is damaged from these conditions, the tissue starts to quickly produce new and enlarged cells, which narrows pulmonary arteries. This increases the pressure inside them. The high pressure in these arteries resists the heart’s effort to pump through them and the blood flow between the heart and lungs is reduced. The right side of the heart then must overcome the resistance and work harder to push the blood through the pulmonary arteries into the lungs. Over time, the right ventricle becomes thickened and enlarged and heart failure develops.

The gene therapy that Dr. Hajjar developed uses a modified adeno-associated viral-vector that is derived from a parvovirus. It works by introducing a healthy SERCA2a gene into cells, but this gene does not incorporate into a patient’s chromosome, according to the study’s lead author, Lahouaria Hadri, PhD, an Instructor of Medicine in Cardiology at Icahn School of Medicine at Mount Sinai.

“The clinical trials in congestive heart failure have shown already that the gene therapy is very safe,” says Dr. Hadri. Between 40-50 percent of individuals have antecedent antibodies to the adeno-associated vectors, so potential patients need to be screened before gene therapy to make sure they are eligible to receive the vectors. In patients without antibodies, the restorative enzyme gene therapy does not cause an immune response, according to Dr. Hadri.

The clinical application of the gene therapy for patients with PAH will most likely differ from those with heart failure. The replacement gene needs to be injected through the coronary arteries of heart failure patients using catheters, while in PAH patients, the gene will need to be administered through inhalation.

This study was supported by National Institutes of Health grants (K01HL103176, K08111207, R01 HL078691, HL057263, HL071763, HL080498, HL083156, and R01 HL105301).

Other study co-authors include Razmig G. Kratlian, MD, Ludovic Benard, PhD, Kiyotake Ishikawa, MD, Jaume Aguero, MD, Dennis Ladage, MD, Irene C.Turnbull, MD, Erik Kohlbrenner, BA, Lifan Liang, MD, Jean-Sébastien Hulot, MD, PhD, and Yoshiaki Kawase, MD, from Icahn School of Medicine at Mount Sinai; Bradley A. Maron, MD and the study’s co-senior author Jane A. Leopold, MD, from Brigham and Women’s Hospital and Harvard Medical School in Boston, MA; Christophe Guignabert, PhD, from Hôpital Antoine-Béclère, Clamart, France; Peter Dorfmüller, MD, PhD, and Marc Humbert, MD, PhD, both of the Hôpital Antoine-Béclère and INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France; Borja Ibanez, MD, from Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain; and Krisztina Zsebo, PhD, of Celladon Corporation, San Diego, CA.

  • Dr. Hajjar and co-author Dr. Zsebo, have ownership interest in Celladon Corporation, which is developing AAV1.SERCA2a for the treatment of heart failure. Also,
  • Dr. Hajjar and co-authors Dr. Kawase and Dr. Ladage hold intellectual property around SERCA2a gene transfer as a treatment modality for PAH. In addition,
  • co-author Dr. Maron receives funding from Gilead Sciences, Inc. to study experimental pulmonary hypertension.
  • Other study co-authors have no financial interests to declare.

Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension

  1. Lahouaria Hadri, PhD;
  2. Razmig G. Kratlian, MD;
  3. Ludovic Benard, PhD;
  4. Bradley A. Maron, MD;
  5. Peter Dorfmüller, MD, PhD;
  6. Dennis Ladage, MD;
  7. Christophe Guignabert, PhD;
  8. Kiyotake Ishikawa, MD;
  9. Jaume Aguero, MD;
  10. Borja Ibanez, MD;
  11. Irene C. Turnbull, MD;
  12. Erik Kohlbrenner, BA;
  13. Lifan Liang, MD;
  14. Krisztina Zsebo, PhD;
  15. Marc Humbert, MD, PhD;
  16. Jean-Sébastien Hulot, MD, PhD;
  17. Yoshiaki Kawase, MD;
  18. Roger J. Hajjar, MD*;
  19. Jane A. Leopold, MD*

+Author Affiliations

  1. From the Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (L.H., R.G.K., L.B., D.L., K.I., J.A., I.C.T., E.K., L.L., J.-S.H., Y.K., R.J.H.); Cardiovascular Medicine Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (B.A.M., J.A.L.); Hôpital Antoine-Béclère, Clamart, France (P.D., C.G., M.H.); INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France (P.D., M.H.); Fundación Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain (B.I.); and Celladon Corporation, San Diego, CA (K.Z.).
  1. Correspondence to Lahouaria Hadri, PhD, Cardiovascular Research Center, Box 1030, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, New York, NY 10029. E-mail lahouaria.hadri@mssm.edu


Background—Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.

Methods and Results—SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline.

Conclusions—Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.

Key Words:

  • Received January 24, 2013.
  • Accepted June 13, 2013.


Circulation.2013; 128: 512-523 Published online before print June 26, 2013,doi: 10.1161/​CIRCULATIONAHA.113.001585

Part III: Cardiac Gene Therapy: Percutaneous Intra-coronary Artery Infusion for Heart Failure

Etiology of Heart Failure

  • Alcoholic
  • Hypertensive
  • Idiopathic
  • Inflammatory
  • Ischemic
  • Pregnancy-related
  • Toxic
  • Valvular Heart DIsease

Administration of Cardiac Gene Therapy for Heart Failure: via Percutaneous Intra-coronary Artery Infusion

  • Gene delivery to viable myocardium

dominance and coronary artery anatomy from angiography determines infusion scenario

  • Antegrade epicardial coronary artery infusion over 10 minutes

60 mL divided into 1,2,3 infusions depending on anatomy

Delivered via commercially available angiographic injection system & guide or diagnostic catheters

Dr. Roger J. Hajjar of the Mount Sinai School of Medicine will present at the ASGCT 15th Annual Meeting during a Scientific Symposium entitled: Cell and Gene Therapy in Cardiovascular Disease on Wednesday, May 16, 2012 at 8:00 am. Below is a brief preview of his presentation.

Roger J. Hajjar, MD

Mount Sinai School of Medicine

New York, NY

Novel Developments in Gene Therapy for Cardiovascular Diseases

Chronic heart failure is a leading cause of hospitalization affecting nearly 6 million people in the U.S. with 670,000 new cases diagnosed every year. Heart failure leads to about 280,000 deaths annually.

Congestive heart failure remains a progressive disease with a desperate need for innovative therapies to reverse the course of ventricular dysfunction. The most common symptoms of heart failure are shortness of breath, feeling tired and swelling in the ankles, feet, legs and sometimes the abdomen. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology have placed heart failure within reach of gene-based therapies.

One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which controls Ca2+ handling in cardiac myocytes on a beat to beat basis. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a).

Over the last ten years we have undertaken a program of targeting important calcium cycling proteins in experimental models of heart by somatic gene transfer. This has led to the completion of a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated vector (AAV) type 1 carrying SERCA2a. In this Phase I trial, there was evidence of clinically meaningful improvements in functional status and/or cardiac function which were observed in the majority of patients at various time points. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation and recent completion of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients. In the phase 2 trial, gene transfer of SERCA2a was found to be safe and associated with benefit in clinical outcomes, symptoms, functional status, NT-proBNP and cardiac structure.

The 12 month data presented showed that heart failure, which is a progressive disease, became stabilized in high dose AAV1.SERCA2a-treated patients: heart failure symptoms, exercise tolerance, serum biomarkers and cardiac function essentially improved or remained the same while these parameters deteriorated substantially in patients treated with placebo and concurrent optimal drug and device therapy. More recently, the 2-year CUPID data from long-term follow-up demonstrate a durable benefit in preventing major cardiovascular events.

The recent successful and safe completion of the CUPID trial along with the start of more recent phase 1 trials usher a new era for gene therapy for the treatment of heart failure. Furthermore, novel AAV derivatives with high cardiotropism and resistant to neutralizing antibodies are being developed to target a large number of cardiovascular diseases.


Power Point Presentation on Cardiac Gene Therapy –



Gene Therapy for Heart Failure

  1. Lisa Tilemann,
  2. Kiyotake Ishikawa,
  3. Thomas Weber,
  4. Roger J. Hajjar

+Author Affiliations

  1. From the Cardiovascular Research Center, Mount Sinai Medical Center, New York, NY.
  1. Correspondence to Roger J. Hajjar, MD, Mount Sinai Medical Center, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail roger.hajjar@mssm.edu


Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today’s science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.

Circulation Research.2012; 110: 777-793 doi: 10.1161/​CIRCRESAHA.111.252981

Key Words:

  • Received December 8, 2011.
  • Revision received January 29, 2012.
  • Accepted January 30, 2012.


With a better understanding of the molecular mechanisms associated with heart failure and improved vectors with cardiotropic properties, gene therapy can now be considered as a viable adjunctive treatment to mechanical and pharmacological therapies for heart failure. In the coming years, more targets will emerge that are amenable to genetic manipulations, along with more advanced vector systems, which will undoubtedly lead to safer and more effective clinical trials in gene therapy for heart failure.


Figure 1.

AAV entry. 1 indicates receptor binding and endocytosis; 2, escape into cytoplasm; 3, nuclear import; 4, capsid disassembly; 5, double-strand synthesis; and 6, transcription.


Figure 2.

Generation of mutant AAV library and directed evolution to identify cardiotropic AAVs. A, Creation of a library of AAVs through DNA shuffling.B, Selection of cardiotropic AAVs through directed evolution.


Figure 3.

Antegrade coronary artery infusion. A, Coronary artery infusion. The vector is injected through a catheter without interruption of the coronary flow. B, Coronary artery infusion with occlusion of a coronary artery: The vector is injected through the lumen of an inflated angioplasty catheter. C, Coronary artery infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected through an inflated angioplasty catheter and resides in the coronary circulation until both balloons are deflated.


Figure 4.

V-Focus system and retrograde coronary venous infusion. A, Recirculating antegrade coronary artery infusion: The vector is injected into a coronary artery, collected from the coronary sinus and after oxygenation readministered into the coronary artery. B, Retrograde coronary venous infusion with simultaneous blocking of a coronary artery and a coronary vein: The vector is injected into a coronary vein and resides in the coronary circulation until both balloons are deflated.


Figure 5.

Direct myocardial injection and pericardial injection. A, Percutaneous myocardial injection: The vector is injected with an injection catheter via an endocardial approach.B, Surgical myocardial injection: The vector is injected via an epicardial approach. C, Percutaneous pericardial injection: The vector is injected via a substernal approach.


Figure 6.

Excitation-contraction coupling in cardiac myocytes provides multiple targets for gene therapy.



Articles citing this article

  • ‘Ryanopathy’: causes and manifestations of RyR2 dysfunction in heart failureCardiovasc Res. 2013;98:240-247,
  • Up-regulation of sarcoplasmic reticulum Ca2+ uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2Cardiovasc Res. 2013;98:297-306,
  • Myocardial Delivery of Stromal Cell-Derived Factor 1 in Patients With Ischemic Heart Disease: Safe and PromisingCirc. Res.. 2013;112:746-747,
  • Circulation Research Thematic Synopsis: Cardiovascular GeneticsCirc. Res.. 2013;112:e34-e50,
  • Gene and cytokine therapy for heart failure: molecular mechanisms in the improvement of cardiac functionAm. J. Physiol. Heart Circ. Physiol.. 2012;303:H501-H512,
  • Ryanodine Receptor Phosphorylation and Heart Failure: Phasing Out S2808 and “Criminalizing” S2814Circ. Res.. 2012;110:1398-1402,


For 154 References on Cardiac Gene Therapy


Read Full Post »

Larry H Bernstein, MD, Writer, Curator
http://pharmaceutical intelligence.com/2013/06/22/ Demythologizing sharks, cancer, and shark fins/lhbern

Screen Shot 2021-07-19 at 6.26.48 PM

Word Cloud By Danielle Smolyar

Sharks have survived some 400 million years on Earth. Could their longevity be due in part to an extraordinary resistance to cancer and other diseases? If so, humans might someday benefit from the shark’s secrets—but leading researchers caution that today’s popular shark cartilage “cancer cures” aren’t part of the solution.

The belief that sharks do not get cancer is not supported in fact, but it is the basis for decimating a significant part of the shark population for shark fins, and for medicinal use.  The unfortunate result is that there is no benefit.

A basis for this thinking is that going back to the late 1800s, sharks have been fished commercially and there have been few reports of anything out of the ordinary when removing internal organs or preparing meat for the marketplace.  In addition, pre-medical students may have dissected dogfish sharks in comparative anatomy, but you don’t see reports of cancerous tumors.

Carl Luer of the MOTE Marine Laboratory’s Center for Shark Research in Sarasota, Florida, has been studying sharks’ cancer resistance for some 25 years.  Systematic surveys of sharks are difficult to conduct, as capturing the animals in large numbers is time-consuming, and cancer tests would likely require the deaths of large numbers of sharks. Of the thousands of fish tumors in the collections of the Smithsonian Institution, only about 15 are from elasmobranchs, and only two of these are thought to have been malignant.

Scientists have been studying cancerous tumors in sharks for 150 years.

The first chondrichthyes’ (cartilaginous fishes, including sharks) tumor was found on a skate and recorded by Dislonghamcps in 1853. The first shark tumor was recorded in 1908. Scientists have since discovered benign and cancerous tumors in 18 of the 1,168 species of sharks. Scarcity of studies on shark physiology has perhaps allowed this myth to be accepted as fact for so many years.

In April 2000, John Harshbarger and Gary Ostrander countered this shark myth with a presentation on 40 benign and cancerous tumors known to be found in sharks, and soon after a blue shark was found with cancerous tumors in both its liver and testes. Several years later a cancerous gingival tumor was removed from the mouth of a captive sand tiger shark, Carcharias Taurus. Advances in shark research continue to produce studies on types of cancer found in various species of shark.  Sharks, like fish, encounter and take in large quantities of environmental pollutants, which may actually make them more susceptible to tumorous growth. Despite recorded cases of shark cancer and evidence that shark cartilage has no curative powers against cancer sharks continue to be harvested for their cartilage.

Sharks and their relatives, the skates and rays, have enjoyed tremendous success during their nearly 400 million years of existence on earth, according to Dr. Luer. He points out that one reason for this certainly is their uncanny ability to resist disease. Sharks do get sick, but their incidence of disease is much lower than among the other fishes. While statistics are not available on most diseases in fishes, reptiles, amphibians, and invertebrates, tumor incidence in these animals is carefully monitored by the Smithsonian Institution in Washington, D.C.

The Smithsonian’s enormous database, called the Registry of Tumors in Lower Animals, catalogs tissues suspected of being tumorous, including cancers, from all possible sources throughout the world. Of the thousands of tissues in the Registry, most of them are from fish but only a few are from elasmobranchs. Only 8 to 10 legitimate tumors are among all the shark and ray tissues examined, and only two of these are thought to have been malignant.

An observation by Gary Ostrander, a Professor at Johns Hopkins University, is that there may be fundamental differences in shark immune systems so that they aren’t as prone to cancer.  The major thrust of the Motes research focuses on the immunity of sharks and their relatives the skates and rays. While skates aren’t as interesting to the public as their shark relatives, their similar biochemical immunology and their ability to breed in captivity make them perhaps more vital to Luer’s lab work.   The result is to study the differences and similarities to the higher animals, and what might possibly be the role of the immune system in their low incidence of disease.

This low incidence of tumors among the sharks and their relatives has prompted biochemists and immunologists at Mote Marine Laboratory (MML) to explore the mechanisms that may explain the unusual disease resistance of these animals. To do this, they established the nurse shark and clearnose skate as laboratory animals. They designed experiments to see whether tumors could be induced in the sharks and skates by exposing them to potent carcinogenic (cancer-causing) chemicals, and then monitored pathways of metabolism or detoxification of the carcinogens in the test animals. While there were similarities and differences in the responses when compared with mammals, no changes in the target tissues or their genetic material ever resulted in cancerous tumor formation in the sharks or skates.

The chemical exposure studies led to investigations of the shark immune system. As with mammals, including humans, the immune system of sharks probably plays a vital role in the overall health of these animals. But there are some important differences between the immune arsenals of mammals and sharks. The immune system of mammals typically consists of two parts which utilize a variety of immune cells as well as several classes of proteins called immunoglobulins (antibodies).

Compared to the mammalian system, which is quite specialized, the shark immune system appears primitive but remarkably effective. Sharks apparently possess immune cells with the same functions as those of mammals, but the shark cells appear to be produced and stimulated differently. Furthermore, in contrast to the variety of immunoglobulins produced in the mammalian immune system, sharks have only one class of immunoglobulin (termed IgM). This Immunoglobulin normally circulates in shark blood at very high levels and appears to be ready to attack invading substances at all times.

Another difference lies in the fact that sharks, skates, and rays lack a bony skeleton, and so do not have bone marrow. In mammals, immune cells are produced and mature in the bone marrow and other sites, and, after a brief lag time, these cells are mobilized to the bloodstream to fight invading substances. In sharks, the immune cells are produced in the spleen, thymus and unique tissues associated with the gonads (epigonal organ) and esophagus (Leydig organ). Some maturation of these immune cells occurs at the sites of cell production, as with mammals. But a significant number of immune cells in these animals actually mature as they circulate in the bloodstream. Like the ever-present IgM molecule, immune cells already in the shark’s blood may be available to respond without a lag period, resulting in a more efficient immune response.

Research was being carried out during the 1980’s at the Massachusetts Institute of Technology (MIT) and at Mote Marine Laboratory designed to understand how cartilage is naturally able to resist penetration by blood capillaries. If the basis for this inhibition could be identified, it was reasoned, it might lead to the development of a new drug therapy. Such a drug could control the spread of blood vessels feeding a cancerous tumor, or the inflammation associated with arthritis.

The results of the research showed only that a very small amount of an active material, with limited ability to control blood vessel growth, can be obtained from large amounts of raw cartilage. The cartilage must be subjected to several weeks of harsh chemical procedures to extract and concentrate the active ingredients. Once this is done, the resulting material is able to inhibit blood vessel growth in laboratory tests on animal models, when the concentrated extract is directly applied near the growing blood vessels.  One cannot assume that comparable material in sufficient amount and strength is released passively from cartilage when still in the animal to inhibit blood vessel growth anywhere in the body.

Tumors release chemicals stimulating the capillary growth so a nutrient-rich blood supply is created to feed the tumorous cells. This process is called angiogenesis. If scientists can control angiogenesis, they could limit tumor growth. Cartilage lacks capillaries running through it. Why should this be a surprise?  Cartilage cells are called chondrocytes, and they fuction to produce a acellular interstitial matrix consisting of hyaluronan (complex carbohydrate formed from hyaluronic acid and chondroitin sulfate) which is protective of interlaced collagen.   Early research into the anti-angiogenesis properties of cartilage revealed that tiny amounts of proteins could be extracted from cartilage, and, when applied in concentration to animal tumors, the formation of capillaries and the spread of tumors was inhibited.

Henry Brem and Judah Folkman from the Johns Hopkins School of Medicine first noted that cartilage prevented the growth of new blood vessels into tissues in the 1970s. The creation of a blood supply, called angiogenesis, is a characteristic of malignant tumors, as the rapidly dividing cells need lots of nutrients to continue growing.  It is valuable to consider that these neovascular generating cells are not of epithelial derivation, but are endothelial and mesenchymal. To support their very high metabolism, tumors secrete a hormone called ‘angiogenin’ which causes nearby blood vessels to grow new branches that surround the tumor, bringing in nutrients and carrying away waste products

Brem and Folkman began studying cartilage to search for anti-angiogenic compounds. They reasoned that since all cartilage lacks blood vessels, it must contain some signaling molecules or enzymes that prevent capillaries from forming. They found that inserting cartilage from baby rabbits alongside tumors in experimental animals completely prevented the tumors from growing. Further research showed calf cartilage, too, had anti-angiogenic properties.

A young researcher by the name of Robert Langer repeated the initial rabbit cartilage experiments, except this time using shark cartilage. Indeed, shark cartilage, like calf and rabbit cartilage, inhibited blood vessels from growing toward tumors. Research by Dr. Robert Langer of M.I.T. and other workers revealed a promising anti-tumor agent obtainable in quantity from shark cartilage. The compound antagonistic to the effects of angiogenin, called ‘angiogenin inhibitor’, inhibits the formation of new blood vessels, neovascularization, that is essential for supporting cancer growth.

The consequence of the”shark myth” is not surprising. An inhabitant of the open ocean, the Silky Shark is ‘hit’ hard by the shark fin and shark cartilage industries – away from the prying eyes of a mostly land bound public. As a consequence of this ‘invisibility’, mortality of Silkies is difficult to estimate or regulate.  North American populations of sharks have decreased by up to 80% in the past decade, as cartilage companies harvest up to 200,000 sharks every month in US waters to create their products. One American-owned shark cartilage plant in Costa Rica is estimated to destroy 2.8 million sharks per year. Sharks are slow growing species compared to other fish, and simply cannot reproduce fast enough to survive such sustained, intense fishing pressure. Unless fishing is dramatically decreased worldwide, a number of species of sharks will go extinct before we even notice.

1.  National Geographic News: NATIONALGEOGRAPHIC.COM/NEWS

2. Do Sharks Hold Secret to Human Cancer Fight?
by Brian Handwerk for National Geographic News.  August 20, 2003

3. Busting Marine Myths: Sharks DO Get Cancer!
by Christie Wilcox   November 9th 2009

Sand tiger shark (Carcharias taurus) at the Ne...

Sand tiger shark (Carcharias taurus) at the Newport Aquarium. (Photo credit: Wikipedia)


Angiogenesis (Photo credit: Wikipedia)

The immune response

The immune response (Photo credit: Wikipedia)

Read Full Post »

Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author: Larry H Bernstein, MD, FCAP

In this article I will address the following article by Dr. SJ Williams.

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies


In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease  Remain Hidden in News and  Analysis) on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease. American Society of  Human Genetics annual 2012 meeting, results of DNA sequencing studies reporting on genetic variants and links to high risk type 2 diabetes and heart disease, part of an international effort to determine the genetic events contributing to complex, common diseases like diabetes.
The key point is that these disease links are challenged by the identification of genetic determinants that do not follow Mendelian Genetics.  There are many disease associated gene variants, and they have not been deleted as a result of natural selection.  In the case of diabetes (type 2), the genetic risk is a low as 26%.

Gene-wide-association studies (GAWS) have identified single nucleotide polymorphisms (SNPs) with associations for common diseases, most of these individually carry only only 20-40% of risk. This is not sufficient for prediction
and use in personalized  treatment.

What is the implication of this.  Researchers have gone to exome-sequencing and  to whole genome sequencing for answers. SNPs can be easily done  by microarray, and in a clinic setting. GWAS is difficult and has inherent complexity, and it has had high cost of use. But the cost of the technology has been dropping precipitously. Technology is being redesigned for more rapid diagnosis and use in clinical research and personalized medicine.  It appears that this is not  yet a game changer.

My own thinking is that the answer doesn’t  fully lie in the genome sequencing, but that it must turn on the very large weight of importance in the regulatory function in the genome, that which was once “considered” dark matter.  In the regulatory function you have a variety of interactions and adaptive changes to the proximate environment, and this is a key to the nascent study of metabolomics.

Three projects highlighted are:
1.  National Heart, Lung and Blood Institute Exome Sequencing Project (ESP)[2]: heart, lung, blood

  • A majority of variants linked to any disease are rare
  • Groups of variants in the same gene confirmed a link between
    APOC3 and risk for early-onset heart attack

2.  T2D-GENES Consortium
3.  GoT2D

  • SNP and PAX4 gene association for type 2 diabetes in East Asians
  • No new rare variants above 1.5% frequency for diabetes


The unsupported conclusion from this has been

  1. the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but   (common unexplained complexity?) each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).
  1. the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, (an alternative complexity situation?) Dickson et al. (2010)  PLoS Biol 2010 8(1):e1000294

The reality is that it has been difficult to associate any variant with prediction of risk, but an alternative approach appears to be intron sequencing and missing information on gene-gene interactions.

Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”.

Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology  http://genomebiology.com/content/11/11/R118 support this notion.  The authors used targeted resequencing
of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.

English: The human genome, categorized by func...

English: The human genome, categorized by function of each gene product, given both as number of genes and as percentage of all genes. (Photo credit: Wikipedia)

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New Center (CEGS) on the Brain: Mental Disorders and the Nervous System

April 16, 2013

NEW YORK (GenomeWeb News) – The National Human Genome Research Institute plans to fund new Centers of Excellence in Genomic Sciences, or CEGS, to create interdisciplinary teams that pursue innovative genome-based approaches to address biomedical problems and to understanding the basis of biological systems.

NHGRI, along with support from the National Institute of Mental Health, expects to provide up to $2 million per year for each of the new CEGS it funds, and plans to award up to four new awards each year.

Although these CEGS may pursue a wide range of research objectives, NIMH will support the program because it wants to fund research using novel genomic approaches that can accelerate the understanding of the genetic basis of mental disorders and the nervous systemNHGRI said on Friday.

The CEGS program was created to use the new knowledge and technologies that resulted from the Human Genome Project and subsequent genomics research to develop new tools, methods, and concepts that apply to human biology and disease.
CEGS grantees are expected to be innovative, to focus on a critical issue in genomic science, to use multiple investigators working under one leader, to work toward a specific outcome, and to tackle challenging aspects of problems that may have impeded previous research efforts.

Further, they are supposed to bolster the pool of professional scientists and engineers who are trained in genomics through offering educational programs, and they are expected to address the shortage of scientists from underrepresented minority communities by developing recruiting programs that encourage minority community members to become independent genomics investigators.

The technologies and methods the CEGS investigators develop should be applicable to a wide range of cell types and organisms, and they should be scalable and expandable so they may apply to other model systems, according to NHGRI’s funding opportunity announcement.

Recent CEGS centers include

  • Caltech’s Center for In Toto Genomic Analysis of Vertebrate Development;
  • Harvard University’s Center for Transcriptional Consequences of Human Genetic Variation;
  • Johns Hopkins University’s Center for the Epigenetics of Common Human Disease;
  • Stanford University’s Center for the Genomic Basis of Vertebrate Diversity;
  • Arizona State University’s Microscale Life Sciences Center;
  • Medical College of Wisconsin, Milwaukee’s Center of Excellence in Genomics Science;
  • The University of North Carolina at Chapel Hill‘s CISGen center;
  • The Broad Institute’s Center for Cell Circuits;
  • Yale University’s Center for the Analysis of Human Genome Using Integrated Technologies; and
  • Dana-Farber Cancer Institute‘s Center for Genomic Analysis of Network Perturbations in Human Disease.


Center for In Toto Genomic Analysis of Vertebrate Development

P50 HG004071
Marianne Bronner-Fraser
California Institute of Technology, Pasadena, Calif.

This Center of Excellence in Genomic Science (CEGS) assembles a multidisciplinary group of investigators to develop innovative technologies with the goal of imaging and mutating every developmentally important vertebrate gene. Novel “in toto imaging” tools make it possible to use a systems-based approach for analysis of gene function in developing vertebrate embryos in real time and space. These tools can digitize in vivo data in a systematic, high-throughput, and quantitative fashion. Combining in toto imaging with novel gene traps permits a means to rapidly screen for developmentally relevant expression patterns, followed by the ability to immediately mutagenize genes of interest. Initially, key technologies will be developed and tested in the zebrafish embryo due to its transparency and the ability to obtain rapid feedback. Once validated, these techniques will be applied to an amniote, the avian embryo, due to several advantages including accessibility and similarity to human embryogenesis. Finally, to monitor alterations in gene expression in normal and mutant embryos, we will develop new techniques for in situ hybridization that permit simultaneous analysis of multiple marker genes in a sensitive and potentially quantitative manner. Our goal is to combine real time analysis of gene expression on a genome-wide scale coupled with the ability to mutate genes of interest and examine global alterations in gene expression as a result of gene loss. Much of the value will come from the development of new and broadly applicable technologies. In contrast to a typical technology development grant, however, there will be experimental fruit emerging from at least two vertebrate systems (zebrafish and avian). The following aims will be pursued: Specific Aim 1: Real-time “in toto” image analysis of reporter gene expression; Specific Aim 2: Comprehensive spatiotemporal analysis of gene function of the developing vertebrate embryo using the FlipTrap approach for gene trapping; Specific Aim 3: Design of quantitative, multiplexed ‘hybridization chain reaction’ (HCR) amplifiers for in vivo imaging with active background suppression; Specific Aim 4: Data analysis and integration of data sets to produce a “digital” fish and a “digital” bird. The technologies and the resulting atlases will be made broadly available via electronic publication.

Center Web Site: California Institute of Technology Center of Excellence in Genomic Science

Top of page

Causal Transcriptional Consequences of Human Genetic Variation

P50 HG005550
George M. Church
Harvard University, Cambridge, Mass.

The Center for Transcriptional Consequences of Human Genetic Variation (CTCHGV) will develop innovative and powerful genetic engineering methods and use them to identify genetic variations that causally control gene transcription levels. Genome Wide Association Studies (GWAS) find many variations associated with disease and other phenotypes, but the variations that may actually cause these conditions are hard to identify because nearby variations in the same haplotype blocks consistently co-occur with them in human populations, so that specifically causative ones cannot be distinguished. About 95% of GWAS variations are not in gene coding regions, and many of these presumably associate with altered gene expression levels. CTCHGV will identify the variations that directly control gene expression by engineering precise combinations of changes to gene regulatory regions that break down the haplotype blocks, allowing each variations’ effect on gene expression to be discerned independently of the others. To perform this analysis, CTCHGV will extract ~100kbps gene regulatory regions from human cell samples, create precise variations in them in E. coli, and re-introduce the altered regions back into human cells, using zinc finger nucleases (ZFNs) to efficiently induce recombination. CTCHGV will target 1000 genes for this analysis (Aim 1), and will use human induced Pluripotent Stem cells (iPS) to study the effects of variations in diverse human cell types (Aim 2). To explore the effects of variations in complex human tissues, CTCHGV will develop methods of measuring gene expression at transcriptome-wide levels in many single cells, including in situ in structured tissues (Aim 3). Finally, CTCHGV will develop novel advanced technologies that integrate DNA sequencing and synthesis to construct thousands of large DNA constructs from oligonucleotides, that enable very precise targeting and highly efficient performance of ZFNs, and that enable cells to be sorted on the basis of morphology as well as fluorescence and labeling (Aim 4). CTCHGV will also develop direct oligo-mediated engineering of human cells, and create “marked allele” iPS that will enable easy ascertainment of complete exon distributions for many pairs of gene alleles in many cell types.

Center Web Site: Center for Causal Transcriptional Consequences of Human Genetic Variation (CTCHGV)

Top of page

Center for the Epigenetics of Common Human Disease

P50 HG003233
Andrew P. Feinberg
Johns Hopkins University, Baltimore
(co-funded by National Institute of Mental Health)

Epigenetics, the study of non-DNA sequence-related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual’s genetic background, the environment, aging, and disease. The Center for the Epigenetics of Common Human Disease was created in 2004 to begin to develop the interface between epigenetics and epidemiologic-based phenotype studies, recognizing that epigenetics requires new ways of thinking about disease. We created a highly interdisciplinary group of faculty and trainees, including molecular biologists, biostatisticians, epidemiologists, and clinical investigators. We developed novel approaches to genome-wide DNA methylation (DNAm) analysis, allele-specific expression, and new statistical epigenetic tools. Using these tools, we discovered that most variable DNAm is in neither CpG islands nor promoters, but in what we term “CpG island shores,” regions of lower CpG density up to several kb from islands, and we have found altered DNAm in these regions in cancer, depression and autism. In the renewal period, we will develop the novel field of epigenetic epidemiology, the relationship between epigenetic variation, genetic variation, environment and phenotype. We will continue to pioneer genome-wide epigenetic technology that is cost effective for large scale analysis of population-based samples, applying our knowledge from the current period to second-generation sequencing for epigenetic measurement, including DNAm and allele-specific methylation. We will continue to pioneer new statistical approaches for quantitative and binary DNAm assessment in populations, including an Epigenetic Barcode. We will develop Foundational Epigenetic Epidemiology, examining: time-dependence, heritability and environmental relationship of epigenetic marks; heritability in MZ and DZ twins; and develop an epigenetic transmission disequilibrium test. We will then pioneer Etiologic Epigenetic Epidemiology, by integrating novel genome-wide methylation scans (GWMs) with existing Genome-Wide Association Study (GWAS) and epidemiologic phenotype data, a design we term Genome-Wide Integrated Susceptibility (GWIS), focusing on bipolar disorder, aging, and autism as paradigms for epigenetic studies of family-based samples, longitudinal analyses, and parent-of-origin effects, respectively. This work will be critical to realizing the full value of previous genetic and phenotypic studies, by developing and applying molecular and statistical tools necessary to integrate DNA sequence with epigenetic and environmental causes of disease.

Center Web Site: Center of Excellence in Genomic Science at Johns Hopkins

Top of page

Genomic Basis of Vertebrate Diversity

P50 HG002568
David M. Kingsley
Stanford University, Stanford, Calif.

The long-term goal of this project is to understand the genomic mechanisms that generate phenotypic diversity in vertebrates. Rapid progress in genomics has provided nearly complete sequences for several organisms. Comparative analysis suggests many fundamental pathways and gene networks are conserved between organisms. And yet, the morphology, physiology, and behavior of different species are obviously and profoundly different. What are the mechanisms that generate these key differences? Are unique traits controlled by few or many genetic changes? What kinds of changes? Are there particular genes and mechanisms that are used repeatedly when organisms adapt to new environments? Can better understanding of these mechanisms help explain dramatic differences in disease susceptibility that also exist between groups? The Stanford CEGS will use an innovative combination of approaches in fish, mice, and humans to identify the molecular basis of major phenotypic change in natural populations of vertebrates. Specific aims include: 1) cross stickleback fish and develop a genome wide map of the chromosomes, genes, and mutations that control a broad range of new morphological, physiological, and behavioral traits in natural environments; 2) test which population genetic measures provide the most reliable “signatures of selection” surrounding genes that are known to have served as the basis of parallel adaptive change in many different natural populations around the world; 3) assemble the stickleback proto Y chromosome and test whether either sex or autosomal rearrangements play an important role in generating phenotypic diversity, or are enriched in genomic regions that control phenotypic change; 4) test whether particular genes and mechanisms are used repeatedly to control phenotypic change in many different vertebrates. Preliminary data suggests that mechanisms identified as the basis of adaptive change in natural fish populations may be broadly predictive of adaptive mechanisms across a surprisingly large range of animals, including humans. Genetic regions hypothesized to be under selection in humans will be compared to genetic regions under selection in fish. Regions predicted to play an important role in natural human variation and disease susceptibility will be modeled in mice, generating new model systems for confirming functional variants predicted from human population genetics and comparative genomics.

Center Web Site: Stanford Genome Evolution Center

Top of page

Microscale Life Sciences Center

P50 HG002360
Deirdre R. Meldrum
Arizona State University, Tempe

Increasingly, it is becoming apparent that understanding, predicting, and diagnosing disease states is confounded by the inherent heterogeneity of in situ cell populations. This variation in cell fate can be dramatic, for instance, one cell living while an adjacent cell dies. Thus, in order to understand fundamental pathways involved in disease states, it is necessary to link preexisting cell state to cell fate in the disease process at the individual cell level.

The Microscale Life Sciences Center (MLSC) at the University of Washington is focused on solving this problem, by developing cutting-edge microscale technology for high throughput genomic-level and multi-parameter single-cell analysis, and applying that technology to fundamental problems of biology and health. Our vision is to address pathways to disease states directly at the individual cell level, at increasing levels of complexity that progressively move to an in vivo understanding of disease. We propose to apply MLSC technological innovations to questions that focus on the balance between cell proliferation and cell death. The top three killers in the United States, cancer, heart disease and stroke, all involve an imbalance in this cellular decision-making process. Because of intrinsic cellular heterogeneity in the live/die decision, this fundamental cellular biology problem is an example of one for which analysis of individual cells is essential for developing the link between genomics, cell function, and disease. The specific systems to be studied are proinflammatory cell death (pyroptosis) in a mouse macrophage model, and neoplastic progression in the Barrett’s Esophagus (BE) precancerous model. In each case, diagnostic signatures for specific cell states will be determined by measuring both physiological (cell cycle, ploidy, respiration rate, membrane potential) and genomic (gene expression profiles by single-cell proteomics, qRT-PCR and transcriptomics; LOH by LATE-PCR) parameters. These will then be correlated with cell fate via the same sets of measurements after a challenge is administered, for instance, a cell death stimulus for pyroptosis or a predisposing risk factor challenge (acid reflux) for BE. Ultimately, time series will be taken to map out the pathways that underlie the live/die decision.

Finally, this information will be used as a platform to define cell-cell interactions at the single-cell level, to move information on disease pathways towards greater in vivo relevance. New technology will be developed and integrated into the existing MLSC Living Cell Analysis cassette system to support these ambitious biological goals including 1) automated systems for cell placement, off-chip device interconnects, and high throughput data analysis with user friendly interfaces; 2) new optical and electronic sensors based on a new detection platform, new dyes and nanowires; and 3) new micromodules for single-cell qRT-PCR, LATE-PCR for LOH including single-cell pyrosequencing, on-chip single-cell proteomics, and single-cell transcriptomics using barcoded nanobeads.

Collaborating InstitutionsFred Hutchison Cancer Research Center, Brandeis University, University of Washington.

Center Web Site: Microscale Life Sciences Center

Top of page

Wisconsin Center of Excellence in Genomics Science

P50 HG004952
Michael Olivier
Medical College of Wisconsin, Milwaukee

The successful completion of the human genome and model organism sequences has ushered in a new era in biological research, with attention now focused on understanding the way in which genome sequence information is expressed and controlled. The focus of this proposed Wisconsin Center of Excellence in Genomics Science is to facilitate understanding of the complex and integrated regulatory mechanisms affecting gene transcription by developing novel technology for the comprehensive characterization and quantitative analysis of proteins interacting with DNA. This new technology will help provide for a genome-wide functional interpretation of the underlying mechanisms by which gene transcriptional regulation is altered during biological processes, development, disease, and in response to physiological, pharmacological, or environmental stressors. The development of chromatin immunoprecipitation approaches has allowed identification of the specific DNA sequences bound by proteins of interest. We propose to reverse this strategy and develop an entirely novel technology that will use oligonucleotide capture to pull down DNA sequences of interest, and mass spectrometry to identify and characterize the proteins and protein complexes bound and associated with particular DNA regions. This new approach will create an invaluable tool for deciphering the critical control processes regulating an essential biological function. The proposed interdisciplinary and multi-institutional Center of Excellence in Genomics Science combines specific expertise at the Medical College of Wisconsin, the University of Wisconsin Madison, and Marquette University. Technological developments in four specific areas will be pursued to develop this new approach: (1) cross-linking of proteins to DNA and fragmentation of chromatin; (2) capture of the protein-DNA complexes in a DNA sequence-specific manner; (3) mass spectrometry analysis to identify and quantify bound proteins; and (4) informatics to develop tools enabling the global analysis of the relationship between changes in protein-DNA interactions and gene expression. The Center will use carefully selected biological systems to develop and test the technology in an integrated genome-wide analysis platform that includes efficient data management and analysis tools. As part of the Center mission, we will combine our technology development efforts with an interdisciplinary training program for students and fellows designed to train qualified scientists experienced in cutting-edge genomics technology. Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities.

Collaborating InstitutionsUniversity of Wisconsin-Madison, Marquette University

Center Web Site: Wisconsin Center of Excellence in Genomic Science

Top of page


P50 MH090338
Fernando Pardo-Manuel de Villena
University of North Carolina, Chapel Hill

p>In this application, we propose a highly ambitious yet realistically attainable goal: to align existing expertise at UNC-Chapel Hill into a CEGS called CISGen. The overarching purpose of CISGen is to develop as a resource and to exploit the utility of the murine Collaborative Cross (CC) mouse model of the heterogeneous human population to delineate genetic and environmental determinants of complex phenotypes drawn from psychiatry, which are among the most intractable set of problems in all of biomedicine. Psychiatric disorders present a paradox – the associated morbidity, mortality, and costs are enormous and yet, despite over a century of scientific study, there are few hard facts about the etiology of the core diseases. Although our GWAS meta- analyses are in progress, early results suggest that strong and replicable findings may be elusive. Therefore, our proposal provides a complementary approach to the study of fundamental psychiatric phenotypes.

We propose a particularly challenging definition of success – we will identify high probability etiological models (which can be realistically complex) and then prove the predictive capacity of these models by generating novel strains of mice predicted to be at very high risk for the phenotype. Once validated, these high confidence models can then be tested in subsequent human studies – we do not propose human extension studies in CISGen but this is achievable for the investigators and their colleagues. Data collected in CISGen would be a valuable resource to the wider scientific community and could be applied to a large set of biological problems and these data can rapidly add to the knowledge base for any new genomewide association study (GWAS) finding. Delivery of sophisticated and user-friendly databases are a key component of CISGen.

Accomplishing this overarching goal requires an exceptional diversity of scientific expertise – psychiatry, human genetics, mouse behavior, mouse genetics, statistical genetics, computational biology, and systems biology. Experts in these disciplines are deeply involved in CISGen and are committed to the projects described herein. Successful integration of these diverse fields is non-trivial; however, all scientists on this application have had extensive interactions over the past five years, already know how to work together, and have a working knowledge of their colleagues’ expertise. UNC-Chapel Hill has an intense commitment to inter- disciplinary genomics research and provides a fertile backdrop for 21st century projects like CISGen.

Collaborating InstitutionsThe Jackson Laboratory, North Carolina State University, University of Texas at Arlington

Center Web Site: Center for Integrated Systems Genomics at UNC (CISGen)

Top of page

Center for Cell Circuits

P50 HG006193
Aviv Regev
The Broad Institute, Inc., Cambridge, Mass.

Systematic reconstruction of genetic and molecular circuits in mammalian cells remains a significant, largescale and unsolved challenge in genomics. The urgency to address it is underscored by the sizeable number of GWAS-derived disease genes whose functions remain largely obscure, limiting our progress towards biological understanding and therapeutic intervention. Recent advances in probing and manipulating cellular circuits on a genomic scale open the way for the development of a systematic method for circuit reconstruction. Here, we propose a Center for Cell Circuits to develop the reagents, technologies, algorithms, protocols and strategies needed to reconstruct molecular circuits. Our preliminary studies chart an initial path towards a universal strategy, which we will fully implement by developing a broad and integrated experimental and computational toolkit. We will develop methods for comprehensive profiling, genetic perturbations and mesoscale monitoring of diverse circuit layers (Aim 1). In parallel, we will develop a computational framework to analyze profiles, derive provisional models, use them to determine targets for perturbation and monitoring, and evaluate, refine and validate circuits based on those experiments (Aim 2). We will develop, test and refine this strategy in the context of two distinct and complementary mammalian circuits. First, we will produce an integrated, multi-layer circuit of the transcriptional response to pathogens in dendritic cells (Aim 3) as an example of an acute environmental response. Second, we will reconstruct the circuit of chromatin factors and non-coding RNAs that control chromatin organization and gene expression in mouse embryonic stem cells (Aim 4) as an example of the circuitry underlying stable cell states. These detailed datasets and models will reveal general principles of circuit organization, provide a resource for scientists in these two important fields, and allow computational biologists to test and develop algorithms. We will broadly disseminate our tools and methods to the community, enabling researchers to dissect any cell circuit of interest at unprecedented detail. Our work will open the way for reconstructing cellular circuits in human disease and individuals, to improve the accuracy of both diagnosis and treatment.

Top of page

Analysis of Human Genome Using Integrated Technologies

P50 HG002357
Michael P. Snyder
Yale University, New Haven, Conn.

We propose to establish a center to build genomic DNA arrays and develop novel technologies that will use these arrays for the large-scale functional analysis of the human genome. 0.3-1.4 kb fragments of nonrepetitive DNA from each of chromosomes 22, 21, 20, 19,7, 17, and perhaps the X chromosome will be prepared by PCR and attached to microscope slides. The arrays will be used to develop technologies for the large-scale mapping of 1) Transcribed sequences. 2) Binding sites of chromosomal proteins. 3) Origins of replication. 4) Genetic mutation and variation. A web-accessible database will be constructed to house the information generated in this study; data from other studies will also be integrated into the database. The arrays and technologies will be made available throughout both the Yale University and the larger scientific community. They will be integrated into our training programs for postdoctoral fellows, graduate students and undergraduates at Yale. We expect these procedures to be applicable to the analysis of the entire human genome and the genomes of many other organisms.

Center Web Site: Yale University Center for Excellence in Genomic Science

Top of page

Genomic Analysis of the Genotype-Phenotype Map

P50 HG002790
Simon Tavaré
University of Southern California, Los Angeles

Our Center, which started in 2003, focused on implications of haplotype structure in the human genome. Since that time, there have been extraordinary advances in genomics: Genome-wide association studies using single nucleotide polymorphisms and copy number variants are now commonplace, and we are rapidly moving towards whole-genome sequence data for large samples of individuals. Our Center has undergone similar dramatic changes. While the underlying theme remains the same — making sense of genetic variation — our focus is now explicitly on how we can use the heterogeneous data produced by modern genomics technologies to achieve such an understanding. The overall goal of our proposal is to develop an intellectual framework, together with computational and statistical analysis tools, for illuminating the path from genotype to phenotype, and for predicting the latter from the former. We will address three broad questions related to this problem: 1) How do we infer mechanisms by which genetic variation leads to changes in phenotype? 2) How do we improve the design, understanding and interpretation of association studies by exploiting prior information? 3) How do we identify general principles about the genotype-phenotype map? We will approach these questions through a series of interrelated projects that combine computational and experimental methods, explored in Arabidopsis, Drosophila and human, and involve a wide range of researchers including molecular biologists, population geneticists, genetic epidemiologists, statisticians, computer scientists, and mathematicians.

Collaborating InstitutionsUniversity of Utah

Center Web Site: The USC Center of Excellence in Genomic Science

Top of page

Genomic Analysis of Network Perturbations in Human Disease

P50 HG004233
Marc Vidal
Dana-Farber Cancer Institute, Boston

Genetic differences between individuals can greatly influence their susceptibility to disease. The information originating from the Human Genome Project (HGP), including the genome sequence and its annotation, together with projects such as the HapMap and the Human Cancer Genome Project (HCGP) have greatly accelerated our ability to find genetic variants and associate genes with a wide range of human diseases. Despite these advances, linking individual genes and their variations to disease remains a daunting challenge. Even where a causal variant has been identified, the biological insight that must precede a strategy for therapeutic intervention has generally been slow in coming. The primary reason for this is that the phenotypic effects of functional sequence variants are mediated by a dynamic network of gene products and metabolites, which exhibit emergent properties that cannot be understood one gene at a time. Our central hypothesis is that both human genetic variations and pathogens such as viruses influence local and global properties of networks to induce “disease states.” Therefore, we propose a general approach to understanding cellular networks based on environmental and genetic perturbations of network structure and readout of the effects using interactome mapping, proteomic analysis, and transcriptional profiling. We have chosen a defined model system with a variety of disease outcomes: viral infection. We will explore the concept that one must understand changes in complex cellular networks to fully understand the link between genotype, environment, and phenotype. We will integrate observations from network-level perturbations caused by particular viruses together with genome-wide human variation datasets for related human diseases with the goal of developing general principles for data integration and network prediction, instantiation of these in open-source software tools, and development of testable hypotheses that can be used to assess the value of our methods. Our plans to achieve these goals are summarized in the following specific aims: 1. Profile all viral-host protein-protein interactions for a group of viruses with related biological properties. 2. Profile the perturbations that viral proteins induce on the transcriptome of their host cells. 3. Combine the resulting interaction and perturbation data to derive cellular network-based models. 4. Use the developed models to interpret genome-wide genetic variations observed in human disease, 5. Integrate the bioinformatics resources developed by the various CCSG members within a Bioinformatics Core for data management and dissemination. 6. Building on existing education and outreach programs, we plan to develop a genomic and network centered educational program, with particular emphasis on providing access for underrepresented minorities to internships, workshop and scientific meetings.

Center Web SiteCenter for Cancer Systems Biology (CCSB) Center of Excellence in Genomic Science

Read Full Post »

Reporters: Aviva Lev-Ari, PhD, RN and Pnina Abir-Am, PhD
Screen Shot 2021-07-19 at 6.13.15 PM
Word Cloud By Danielle Smolyar
Jeffrey L. Sturchio

Senior Partner, Rabin Martin

Jeffrey L. Sturchio is senior partner at Rabin Martin, a global health strategy firm in New York. Prior to joining the firm, he served as president and CEO of the Global Health Council. Before joining the Council, Dr. Sturchio was vice president of Corporate Responsibility at Merck & Co. Inc., president of the Merck Company Foundation and chairman of the U. S. Corporate Council on Africa, whose 150 member companies represent some 85 percent of total US private sector investment in Africa. He is a visiting scholar at the Institute for Applied Economics and the Study of Business Enterprise at Johns Hopkins University, a Fellow of the American Association for the Advancement of Science and a member of the Council on Foreign Relations. He received an AB in history from Princeton University and a PhD in the history and sociology of science from the University of Pennsylvania.

World Cancer Day: Treatment Should Not Be a Luxury
Posted: 02/04/2013 10:20 am
Huffington Post IMPACT
Author: Jeffrey L. Sturchio, Senior Partner, Rabin Martin

co-authored by Cary Adams.

All of us have been touched by cancer, whether personally or through the experience of our families and friends. For those of us living in the developed world, many types of cancer have ceased to be the “dread disease” they once were: Given the remarkable advances in basic science and oncology, it’s more a question of what the best course of treatment is, rather than one of availability or affordability. But for most of the world, access to cancer screening, detection, diagnosis and oncology care is still an unattainable luxury. Considering that nearly half of cancer cases — and 55 percent of the deaths — occur in less developed countries, we need to make progress now.

If left unchecked, the annual economic burden of cancer will be an estimated $458 billion by 2030, according to a study by the World Economic Forum and Harvard School of Public Health. But the human cost of 21.4 million new cases per year by 2030 is, quite simply, unacceptable. In commemoration of World Cancer Day (Today, February 4), we call for the global community to step-up its efforts to address cancer and other NCDs.

Cancers, along with other non-communicable diseases (NCDs) such as diabetes, upper respiratory infections and cardiovascular disease, are the leading causes of mortality around the world. Indeed, the number of cancer deaths alone surpasses those attributed to AIDS, tuberculosis and malaria combined. Once considered illnesses of the wealthy, 80 percent of the estimated 36 million NCD-related deaths actually occur in low- to middle- income countries, according to the World Health Organization. And while a global movement for action on NCDs has been gathering momentum in recent years, much remains to be done.

The Institute for Applied Economics, Global Health and the Study of Business Enterprise at Johns Hopkins University recently released a set of policy briefs that present recommendations for Addressing the Gaps in Global Policy and Research for Non-Communicable Disease. The publication compiles the findings of a Working Group of leading experts in the field and offers a road map of actionable recommendations for reducing the global burden of these diseases.

The report echoes many of the themes put forth by the global cancer community for achieving the goals articulated in the World Cancer Declaration. For starters, there needs to be a multi-sectoral approach to cancer. Governments, civil society, academe and the private sector must work together to leverage strengths and efficiencies to advance efforts to reduce the burden of cancer.

Greater participation by the private sector in a transparent and open way will improve efforts against the disease in coming years. Certainly, private-public partnerships to tackle cancer exist, but greater collaboration among stakeholders is needed. One suggestion may be to develop a knowledge exchange network for oncology researchers in industry and academe to accelerate the rate of progress in discovering and developing new vaccines, personalized medicines, pharmaceuticals and other essential medical technologies. While their most significant role is — and will continue to be — in R&D, the private sector can also lend considerable expertise in systems efficiencies, human resource development and supply chain management, to name just a few areas in which their capabilities can improve the global response to cancer.

Governments need to play a more active role in actively reducing and raising awareness about risk factors for cancer and other NCDs. They need to work with civil society and industry to reduce tobacco and excessive alcohol use, while promoting healthier diets and physical activity at the national and community levels. Again the private sector can play a lead role in improving the health impacts of their products to reduce the global growth in NCDs.

Countries need to make greater investments in building the capacity of local health workers so they are more capable of educating patients about reducing their cancer risk through behavior modification as well as immunization against human papilloma virus (HPV) and hepatitis B (HBV) infections (which can lead to cervical cancer and primary liver cancer, respectively). Health workers are the first line of defense, detecting hallmarks of disease and providing cancer screening, treatment and, when necessary, long-term care. Moreover, countries need to re-evaluate how they can retain health workers who are trained in cancer care. Without them, all interventions become impossible.

Finally, there needs to be greater focus on providing equitable access to screening, early diagnosis and treatment. Self-exams and visual inspection with acetic acid for breast cancer and cervical cancer screening respectively, are two excellent examples of effective, inexpensive, life-saving innovations that can be implemented even in low-resource settings. Integrating these methods into existing primary, reproductive and maternal health service models would help reduce the 750,000 deaths from cervical and breast cancer each year.

It’s a lot of work, but for many of us, cancer hits very close to home. By working together to combat cancer, each doing our part, we can begin to make a difference in the lives of millions — making cancer care and treatment not a luxury, but a reality.

Cary Adams is CEO of the Union for International Cancer Control (UICC), which helps the global health community accelerate the fight against cancer. Its growing membership of over 700 organisations in 155 countries features the world’s major cancer societies, ministries of health and patient groups and includes influential policy makers, researchers and experts in cancer prevention and control. Adams and his team focus on global advocacy to deliver the World Cancer Declaration targets by 2020, running global programs that address key cancer issues and use their membership reach to bring about the exchange of best practice globally. He recently became Chair of the NCD Alliance, a coalition of around 2,000 NGOs working on non-communicable diseases.

Jeffrey L. Sturchio
Doug Ulman

The Global Burden of Cancer

Posted: 02/04/2011 11:44 am
Most of us in developed countries have dwelled in the shadow of cancer. We’ve anxiously awaited a test result, become intimate with chemotherapy for ourselves or a loved one or held vigil at a bedside.

During those intense and often tragic periods, we usually have options — education, treatment, pain relief and sometimes, blessedly, remission and recovery — that is, if we happen to reside in a wealthy country. Not so for millions of others, adults and children alike, in poorer countries where more than 70 percent of all cancer deaths occur yet five percent or less of cancer resources are allocated to the people living there, despite the growing cancer burden.

Cancer is a growing cause of death worldwide. The cancer burden in low- and middle-income countries is increasingly disproportionate. Globally in 2009, there were an estimated 12.9 million cases of cancer, a number expected to double by 2020, with 60 percent of new cases occurring in low- and middle-income countries.

Not only do these countries carry more than half the disease burden, they lack the resources for cancer awareness and prevention, early detection, treatment or palliative options to relieve the staggering pain and human suffering if the disease is untreated — an unthinkable outcome for people who have cancer in rich nations.

Cancer also has the most devastating economic impact of any cause of death in the world, according to the recent landmark report, “The Global Economic Cost of Cancer,” released by the American Cancer Society and Livestrong. Premature deaths and disability from cancer cost the global economy nearly 1 trillion dollars a year. The data from this study provides compelling evidence that balancing the world’s global health agenda to address cancer more effectively will save not only millions of lives, but also billions of dollars.

By making cancer a global priority, as with many other non-communicable diseases, cancer deaths can be prevented an estimated 40 percent or more. This goal is a particular focus of this year’s World Cancer Day(today, February 4). But prevention can only be achieved through investments in awareness and education. Neglect of prevention leads to unaffordable treatment.

Even though tobacco use is the most preventable cause of cancer, lung cancer still kills more people worldwide than any other — a trend likely to surge unless efforts for global tobacco control are greatly accelerated. Tobacco use is responsible for 1.8 million cancer deaths per year, 60 percent in low- and middle-income nations, thanks to the tobacco industry’s unrelenting country-by-country approach to marketing their addictive product, including to youth. Last year, the Australian Broadcasting Corporation won a Global Health Council Excellence in Media Award for its hard-hitting and poignant exposé of tobacco marketing in Indonesia, “80 Million a Day: Big Tobacco’s New Frontier.” We need to cast more light on this invisible killer.

Other preventable risk factors for all cancers are unhealthy lifestyles (including alcohol abuse, inadequate diet and physical inactivity), exposure to occupational (e.g., asbestos) or environmental carcinogens (e.g., indoor air pollution), radiation (e.g., ultraviolet and ionizing radiation) and infections.

Cancers due to infectious diseases account for 8-10 percent of cases in high income countries, but 20-26 percent in developing countries. The human-to-human spread of viruses and bacteria can lead to liver and stomach cancers, lymphomas and leukemia. In addition to infections, many reproductive health diseases are linked to cancer. Strengthening the health systems of developing countries will pave the way for improved vaccine delivery and wider coverage of immunizations that will save lives and protect people’s health.

The Global Health Council and Livestrong call on global partners, allies, donors, policymakers, communities and individuals to work collaboratively to address the treatment expenditure gap and change the trajectory of this tidal wave of cancer. We have a choice – invest now or pay later with significant government spending and the loss of millions of lives and lessened productivity.

Capacity building is essential. Ministries of health, education and finance need to be engaged in developing and supporting plans that include both training of personnel to diagnose and treat cancer patients and strategies to reduce costs and strengthen health systems.

We need to focus on cancer surveillance to set standards to understand better the burden of cancer and the impacts of interventions. We need to implement relevant interventions at scale, including those that draw on successful models that address other diseases. We must rapidly expand information and awareness campaigns on a global scale to reach deeply into affected communities of developing countries. And we need continued investments in research and development for improved knowledge of the science of cancer and better drugs, vaccines and new tools for cancer prevention and control.

Starting today, advocates, governments, non-profits and the private sector must drive new and effective policies, programs and investments. Patients and survivors around the world cannot wait a moment longer for us to advance the global fight against cancer. Failing to act is indefensible — the human and economic costs are too high.

See more information at “Cancer in Developing Countries,” Global Health Council.


Around the globe, from Cape Town to Kathmandu, from Manila to Mexico City, millions will be celebrating the 100th anniversary of International Women’s Day on March 8 — a day to honor the achievements made by and for women. Looking at this milestone through a global health lens, we see an increasingly positive picture, but the view is far from perfect. In fact, we stand at a crossroads.

Globally, we’ve seen a notable decline in maternal deaths from half a million women to 342,000 annually. This is still far too many, but it is an important step in the right direction. Yet this progress is at risk, with mounting efforts underway to deny access to one of the best investments in women’s health: family planning.

In Bangladesh, just last month, a national survey showed a 40 percent drop in maternal deaths during the last decade. One of the contributing factors? Family planning. That is an unprecedented step forward.

Tanzania achieved a 21.5 percent drop in maternal deaths during the last five years, precipitated in part by increased access to and enthusiastic use of modern contraception. Another step forward.

In places like Ghana and Ethiopia, women every day have access to more contraceptive options — another step forward — as they endeavor to plan their families and define their futures. Women like Ayera Kabele, an ambitious 30-year old in Addis Ababa. She married in her early 20s and had a child soon thereafter. But she was also a student who wanted to finish college — a dream achieved because she was able to delay having another child by using an IUD. Four years later, degree in hand, Ayera and her husband were ready for their second child — another dream achieved. Yet another step forward.

This scenario between couples plays out every day around the world — including here in the United States. These are universal conversations about when to start a family and how many children to have. Anyone who has been a party to one can appreciate how vital they are to the health and well-being not only of women, but also of their families as well.

Why is that? In addition to saving women from death and injury during pregnancy or childbirth, saving mothers’ lives saves babies’ lives. Family planning also boosts women’s economic empowerment and creates an environment where children have a better chance not only to survive, but also to thrive. Strong and healthy families lead to stronger and more stable communities, in a virtuous cycle toward prosperity for nations.

We know that up to one-third of maternal deaths could be prevented if every woman who wanted to use contraception to limit or space her births was able to do so. In part, this is due to fewer unwanted pregnancies — especially when women have no other options — and thus to fewer women seeking abortion to end them. Mostly, though, it’s because every pregnancy and childbirth poses risks, especially where medical care is inadequate, if it exists at all. This is how family planning saves lives — and more.

Yet flying in the face of mounting evidence, there is a real risk that the United States foreign assistance budget will include drastic cuts to international family planning — the catalyst to so much good in countless communities worldwide. Indeed, at a moment when every budget dollar must be used as efficiently and effectively as possible, few investments pay better long-term dividends than family planning.

Just four years remain until the deadline for achieving the Millennium Development Goals (MDGs) set by the United Nations. A report released last year rated access to reproductive health care as low or moderate in 70 percent of the regions surveyed. This is not acceptable.

There have been strong policy and funding commitments made in the United States’ Global Health Initiative as well as at the United Nations (U.N.) to bolster access to and support for family planning as vital investments to improve the lives of women and families worldwide. The year 2010 also saw the launch of the first-ever U.N.’s Global Strategy for Women’s and Children’s Health and ongoing efforts by the State Department’s Office on Global Women’s Issues to link foreign policy with women’s rights. There is much reason for optimism.

As we mark the centennial of International Women’s Day, supporters of women’s health worldwide must continue to advocate for family planning and reproductive health services, which have done so much for women and girls in the U.S. and in so many countries around the world.

See the Global Health Council position paper on Maternal, Newborn, Child and Reproductive Health.

 Follow Jeffrey L. Sturchio on Twitter: www.twitter.com/globalhealthorg

Read Full Post »

English: reaction of the lactate dehydrogenase...

English: reaction of the lactate dehydrogenase: pyruvate (left) is oxidized to lactate (right) by expense of NADH Deutsch: Reaktionsmechanismus der Lactatdehydrogenase: normalerweise wird Pyruvat (links) wird mittels NADH zu Lactat (rechts) oxidiert (Photo credit: Wikipedia)

Remembering a Great Scientist among Mentors

Author: Larry H. Bernstein, MD

Article ID #20: Portrait of a great scientist and mentor: Nathan Oram Kaplan. Published on 1/26/2013

WordCloud Image Produced by Adam Tubman


N a t h a n O r a m K a p l a n (1917-1986) This is a portrait of my experience and a tribute to a giant of metabolic discovery in the third quarter of the 20th century.

Part I. My interest leading up to my experience with Nathan O. Kaplan

A. Graduate School Experience

Working under Harry Maisel, my teacher and mentor led to a thesis on “The Ontogeny of the Crystalline Proteins of the Bovine Lens.” But while I was carrying out those studies, I also investigated the “Changes in the Isoenzymes of Lactic Dehydrogenase”. This required the use of starch gel electrophoresis introduced by David Poulik and Oliver Smithies, prior to the use of polyacrylamide. The gels were bisected and stained for protein or for enzymatic activity.
There was a controversy at that time over a view held by Elliott Vessell and NO Kaplan’s argument that the LDH is a tetramer composed of M-type and H-type subunits polymerized that have metabolically different roles.

  •  The lens of the eye and circulating mature red cells depend on glycolysis for 86% of their energy, and the reminder is in the pentose phosphate shunt (essential for nucleotide and nucleoside synthesis). Mature lens and red cells have a predominantly H4, H3M pattern, so that LD1 and 2 are elevated in hemolysis and in heart attack. The distribution in kidney is a mixture of the medullary and the cortical patterns, as the cortex has a high rate of aerobic glycolysis, and it has a rich vasculature of glomuli capillaries and arterioles.
  • The cardiomyocyte and skeletal muscle both have nuclei, but one has the H4, H3M and the other has M4, M3H predominant pattern.

So it would appear that Kaplan had a better grasp of the problem. One the one hand, he held that the H-type LD subunit is regulatory, while the M-type is not. Renal cortical epithelial cells have a high rate of aerobic glycolysis, aka, mitochondria. On the other hand, he also saw an organ pattern relationship represented by TPN vs DPN, depending on primary role in synthetic activity or high energy utilization.
Functional lactate dehydrogenase are homo or hetero tetramers composed of M and H protein subunits encoded by the LDHA and LDHB genes, respectively:

  1. LDH-1 (4H)—in the heart
  2. LDH-2 (3H1M)—in the reticuloendothelial system
  3. LDH-3 (2H2M)—in the lungs
  4. LDH-4 (1H3M)—in the kidneys, placenta, and pancreas
  5. LDH-5 (4M)—in the liver and striated muscle[2]

B. Postgraduate Medical Education

In residency in Pathology I came under the influence of the late Masahiro Chiga, a pathologist and noted biochemist who had discovered that myokinase is distinguished from adenylate kinase by inhibition with sulfhydryl reagents. He encouraged me to go the University of California, San Diego, where I could learn from from Nate Kaplan. I completed my postgraduate education on an NIH Training Grant in Cardiovascular Pathology under AA Liebow, work withing with Nathan Kaplan, and well prepared in both scientific method and in Pathology with several published papers.

C. The m-type (mitochondrial) malate dehydrogenase

My main research occupation was in work the two major isoenzymes of malate dehydrogenase (c- and m-type) and the nature of a ternary complex of enzyme, oxaloacetate, and DPN (NAD) formed during the forward reaction of OAA to malate generating DPN from DPNH. The regulatory nature of the c- and m-type MDH in hydrogen transfer between the cytoplasm and mitochondrion were of great interest.

D . A full fledged Pathologist/Clinical Pathologist

My focus was on the mitochondrial and cytoplasmic malate dehydrogenases, in hepatoma, in comparative animal life, and in different tissues when I joined Herschel Sidranski in a Department of Pathology at University of South Florida, Tampa.

Part II. About Nate Kaplan

The following material is extracted from these sources:

  1. A biographical memoir, William D. McElroy (National Academy of Sciences, 1994)
  2. Nathan O. Kaplan Papers, 1943-1986. UCSD, Geisel Library. Mandeville Special Collections Library. La Jolla, California 92093-0175. Collection number: MSS 0099.
  3. QUOTATIONS BY William Allison, Morris Friedkin, Martin Kamen, H. A. Barker, David Greenberg, Mary Ellen Jones, and W. P. Jencks are found in a memorial publication dedicated to Nate, and appeared in Analytical Biochemistry 1987;161:229-44.

A. Early and Predoctoral

Kaplan’s formative work with David Greenberg in the Biochemistry Division of the Berkeley medical school, involved studying phosphate utilization, distribution, and turnover in various nutritional states and required extracting, separating, and identifying organic phosphate compounds of metabolic significance. Martin Kamen wrote a brief account of Nate’s stay at Berkeley: Nate’s collaboration with Michael Doudoroff and William Zev Hassid demonstrated that glucose 1-phosphate and fructose were the products of sucrose breakdown by enzymatic transfer of a glucosyl moiety to radioactive phosphate (from EO Lawrence’s lab).B. Postdoctoral workNate attended a microbial metabolism course given by H. A. Barker and at that time Lipmann’s article on phosphate bond energy appeared in Volume 1 of Advances in Enzymology (1941).

In 1945, he focused on coenzyme A as a research associate with Nobel laureate Fritz Lipmann at the MGH. Lipmann had recently shown that the acetylation of sulfanilamide by pigeon liver extracts required a heat-stable factor, which Kaplan purified, now known as coenzyme A. He was also instrumental in determining its structure, and helped establish the universality of coenzyme A in 2-carbon metabolism. Nate, G. David Novelli and Beverly Guirard, soon found that Coenzyme A contained pantothenic acid, and later Shuster and Kaplan found that a phosphate group was attached to the 3′-hydroxyl of the ribose ring of adenylic acid. In the meantime Kaplan and Lipmann found that most of the pantothenate in tissues was present in coenzyme A. For his contributions to the work on coenzyme A, Nate shared the Nutrition Award in 1948 and received the Eli Lily Award in Biochemistry in 1953.

B. McCollum-Pratt Institute

Kaplan and Sidney Colowick (who had just left the Cori laboratory at Washington University in St. Louis) developed a successful and productive collaboration at the University of Illinois prior to their invitation by W.D. McElroy to the McCollum-Pratt Institute at Johns Hopkins University studying the chemistry of the pyridine nucleotide coenzymes and the enzymes that are involved with them. This collaboration led to the founding in 1955 of the classic series, Colowick and Kaplan’s Methods in Enzymology, which had more than 140 volumes in 1986, and continues today.
McElroy recalls the establishment of the McCollum-Pratt Institute at Johns Hopkins. “There was a large gap between European-English biochemistry and that of the United States. Only in 1941 when Lipmann and Kalckar published their famous reviews was ATP introduced widely in the U.S. biochemical literature. Nate spent hours with Dr. Elmer McCollum learning all he could about the history of nutrition and biochemistry. The year that Warburg discovered the requirement of Mg2+ for the triose phosphate dehydrogenase was the same year that McCollum demonstrated it as an essential micronutrient in animals.
Kaplan and Colowick carried out studies on oxidative phosphorylations in
the microbe Pseudomonas aeruginosa, a well-known bacteria with a very high oxidative capacity. Sid and Nate made the interesting discovery that a transfer of hydrogen from the NADPH to NAD was occurring when both pyridine nucleotides were present in the reaction mixture. It was this discovery that led to many efforts to characterize the transhydrogenase that was obviously present in the system.

Work done by Kaplan, Colowick, and Elizabeth Neufeld at the Institute describes discovery of a transhydrogenase from pig heart mitochondria that transfers hydrogen from TPNH (NADPH) to DPN (NAD), which Martin Klingenberg and Lars Ernster showed transfers electrons from NADH to NADP in an energy-dependent reaction.
(From the McCollum-Pratt Institute, The Johns Hopkins University, Baltim,ore,
(Received for publication, April 15, 1953)

In previous communications, an enzyme from Pseudomonas fluorescens has been described, that catalyzes a transfer of electrons between the pyridine nucleotides (1-3). This enzyme, termed pyridine nucleotide transhydrogenase, was shown to promote Reactions 1 to 5.’
(1) TPNH + DPN+ -+ TPN+ + DPNH
(2) TPNH + desamino DPN+ + TPN+ + desamino DPNH
(3) Desamino TPNH + DPN+ -+ desamino TPN+ + DPNH
(4) Desamino DPNH + DPN+ + desamino DPN+ + DPNH
(5) Desamino TPNH + TPN+ 4 desamino TPN+ + TPNH
We have been able to detect the presence of pyridine nucleotide transhydrogenase activity in a number of animal tissues. The present paper deals with the properties and specificity of the animal transhydrogenases, and indicates differences between the animal and bacterial systems.


McElroy had a number of nitrate mutants in Neurospora that could reduce nitrate to nitrite, but the latter would not be further metabolized. Nate had some FAD which led to the eventual discovery that reduced FAD was the immediate electron donor for the reduction of molybdenum and subsequently the reduction of nitrate.
In addition, Nate and Sid found an enzyme which could split NAD at the nicotinamide ribosidic linkage present in relatively large amounts in zinc-deficient Neurospora. The compound was the alpha isomer of NAD, which exhibited very low or no activity with most dehydrogenases. When Nate and Sid studied NADase isolated from mammalian sources they found that the animal enzyme was inhibited by nicotinamides whereas the Neurospora enzyme was quite insensitive to the free vitamin. Leonard Zatman observed that radioactive nicotinamide could be incorporated into NAD and demonstrated that an exchange reaction was occurring.

Following the discovery of Neurospora DPNase, Nate and Sid worked together on enzymes concerned with DPN, particularly the exchange reactions involving ADP ribosyl enzyme and various nicotinamide derivatives. The work on NAD and NADP and the analogs, which they were able to make by the exchange reaction, formed the basis for an intense collaboration between Nate and Colowick concerning the function of these coenzymes in various dehydrogenases.

Using the exchange reaction, Nate was able to prepare the acetylpyridine derivative of NAD, which turned out to be extremely important as it was the compound used later by Nate to compare the biochemistry of various dehydrogenases. The ratio of the activity with DPN and the acetylpyridine analog was a very sensitive measure of the differences of various dehydrogenases in different species and in different organs. The reduced form of the acetylpyridine NAD had an absorption maximum at 375 nm as compared to 340 nm for NADH. This, of course, eventually led to the important research on isozymes.

He studied the isozymes of various dehydrogenases and noted their changes during development. Probably his best-known work in the area was concerned with the M and H isozymes of lactic dehydrogenase, this latter work leading to his interest in cancer metabolism. One of Nate’s great assets was willingness to help anyone in need—graduate students, postdocs, faculty and visiting scientists. While no mention is made of this he brought on a bright high school student, Francis Stolzenbach, who would stay with him for over 20 years.

C. Brandeis University

He established the Graduate Department of Biochemistry at Brandeis University in 1957, in association with Martin Kamen who joined him at Brandeis, and hired carefully selected young assistant professors. Mr. Rosenstiel, a rare individual who preferred to “buy brains, not bricks”, gave $1,000,000 to start the department and supplemented this later with additional support to the department and university. Kaplan and Kamen were able to turn this investment into a 2,300 percent profit from various sources, to provide a strong base of support for the department. The scientific productivity of this fledling department was of a caliber that it gained international recognition in a very short time. Brandeis had only been founded in 1948, and became a major, research oriented university in the sciences in the 1960s.
When he moved to Brandeis, Nate was able to distinguish the heart and muscle lactate dehydrogenase of a given species using NAD analogs. He found that the heart enzyme of one species was much more closely related to the heart enzyme of another species as compared to the muscle enzyme of the same species. This led to the study of changes in lactate dehydrogenase during development in chickens, and it was discovered that the type of LDH that occurred in the embryonic chick breast muscles was actually the heart type. He observed that during development the genes for the M types were being expressed at an increased rate and it became the principal LDH type at the time of hatching. A connection was made to an observation that Markert had reported with regard to the fact that LDH was actually a tetramer. Their results supported the view that there were five forms of LDH consisting of the two parent types, occurring as H4 and M4, with three intermediate hybrid types, which migrated predictably in between H and M forms on polyacrylamide gels.

How did Nate make all this work so well? He somehow led a large and diverse research group that studied the biochemistry of DPN (not NAD) and many other subjects. While he was at Brandeis, he had brought on a key laboratory staff member from Holland, Johannes Everse, who worked with him for 16 years.

Part III. The move to University of California, San Diego

Nate Kaplan came to the new University of California, San Diego in 1968 at the urging of Martin Kamen, with W.D. McElroy as Chancellor. “Nate’s laboratory made important contributions in biochemical research at UCSD. Using NMR, his students and postdoctoral fellows established the conformations of the pyridine nucleotide coenzymes and other nucleotides in aqueous solution. Other important contributions were on the development of matrices for affinity chromatography of enzymes, immobilization of enzymes, and immobilization of ligands for membrane receptors.” These methods of affinity chromatography have led to a revolution in separation technology.
He wrote, “students should not lose sight of the eloquence of the experiments of Warburg because it is the same eloquence which is inherent in the isolation, characterization, and manipulation of genes.”

Read Full Post »

Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #3: Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors. Published on 11/23/2012

WordCloud Image Produced by Adam Tubman

Featured Researcher:

Prof. Beth Murinson, MD, PhD   of Technion’s Rappaport Faculty of Medicine came to Technion after being a professor at Johns Hopkins Medical School. She discusses her research in the field of Neurology and pain management.

Prof. Beth Murinson, MD, PhD, at Technion’s Rappaport Faculty of Medicine, has been a very busy person since coming to Israel in 2010 with her husband and two children. Before Technion she was an associate professor at Johns Hopkins Medical School. A neurologist who specializes in injury to the peripheral nerve, these days Murinson can be found in her laboratory and at Rambam hospital. She conducts research and works on educational projects that are designed to treat patients with acute and persistent pain; teaches medical students, both the Israeli students and those from the USA who are in TeAMS – Technion’s American medical school program; advises medical students in the USA; is an attending neurologist in the Department of Neurology at Rambam Health Care Campus and runs an outpatient clinic specializing in peripheral nerve injuries, chronic neuropathic pain and back injuries.

Murinson’s research is focused on chemotoxic and traumatic injuries to the nerve. Her two main research models address the response of growing peripheral nerve cells to exposure to a common pharmacological agent and deal with nerve injury. She is trying to determine what is the least amount of injury that will produce neuropathic pain; it is important to understand what injuries are painful and which injuries are not. Her goal is to find methodology or treatments that will help prevent induced nerve injury. There are some drugs that are widely used and taken by millions of people that have the potential to harm nerves. She also works in collaboration with the oncology group at Rambam.



“To find methodology or treatments that will help prevent induced nerve injury.”

Murinson’s academic credentials are impressive; she got an early start by graduating high school early and proceeding to receive her Bachelor’s degree in mathematics from Johns Hopkins, a Master’s from UCLA in biomathematics, and an MD/Phd (in physiology) from the University of Maryland, graduating with honors. After, she did her residency in neurology at Yale and she finished her education with a fellowship in neuroelectrophysiology back at Johns Hopkins.

It’s a wonder she found time to write a book.

Take Back Your Back is the volume to read if you are suffering from back pain. The book lets patients know everything they can do to regain control over their lives after a back injury. It provides a wealth of information on what can go wrong with the back and how patients can take charge of their own recovery.



Flaviogeranin, a new neuroprotective compound from Streptomyces sp.

Yoichi Hayakawa, Yumi Yamazaki, Maki Kurita, Takashi Kawasaki, Motoki Takagi and Kazuo Shin-ya


Cerebral ischemic disorders are one of the main causes of death. In brain ischemia, blood flow disruptions limit the supply of oxygen and glucose to neurons, initiating excitotoxic events.

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
The Journal of Antibiotics 63, 379-380 (July 2010) | doi:10.1038/ja.2010.49

Sarcophytolide: a new neuroprotective compound from the soft coral Sarcophyton glaucum.

F A BadriaA N GuirguisS PerovicR SteffenW E MüllerH C Schröder

Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Egypt.
Toxicology (impact factor: 3.68). 12/1998; 131(2-3):133-43.
Bioactivity-guided fractionation of an alcohol extract of the soft coral Sarcophyton glaucum collected from the intertidal areas and the fringing coral reefs near Hurghada, Red Sea, Egypt resulted in the isolation of a new lactone cembrane diterpene, sarcophytolide. The structure of this compound was deduced from its spectroscopic data and by comparison of the spectral data with those of known closely related cembrane-type compounds. In antimicrobial assays, the isolated compound exhibited a good activity towards Staphylococcus aureus, Pseudomonas aeruginosa, and Saccharomyces cerevisiae. Sarcophytolide was found to display a strong cytoprotective effect against glutamate-induced neurotoxicity in primary cortical cells from rat embryos. Preincubation of the neurons with 1 or 10 microg/ml of sarcophytolide resulted in a significant increase of the percentage of viable cells from 33 +/- 4% (treatment of the cells with glutamate only) to 44 +/- 4 and 92 +/- 6%, respectively. Administration of sarcophytolide during the post-incubation period following glutamate treatment did not prevent neuronal cell death. Pretreatment of the cells with sarcophytolide for 30 min significantly suppressed the glutamate-caused increase in the intracellular Ca2+ level ([Ca2+]i). Evidence is presented that the neuroprotective effect of sarcophytolide against glutamate may be partially due to an increased expression of the proto-oncogene bcl-2. The coral secondary metabolite, sarcophytolide, might be of interest as a potential drug for treatment of neurodegenerative disorders.

Pharmacological treatment of Alzheimer disease: From psychotropic drugs and cholinesterase inhibitors to pharmacogenomics

Cacabelos, R., et al.

Drugs Today 2000, 36(7): 415
ISSN 1699-3993
Copyright 2000 Prous Science
CCC: 1699-3993

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more “molecular approach” based on new data on the pathogenic events underlying neurodegeneration in AD.

In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into 4 main categories:

  • primary events (genetic factors, neuronal apoptosis),
  • secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss),
  • tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and
  • quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction).

All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis.

This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment.

  • Stem-cell activation,
  • genetically manipulated cell transplantation,
  • gene therapy and
  • antisense oligonucleotide technology

constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration.

The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.



Dementia is a major problem of health in developed countries. Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50–70% of the cases, followed by vascular dementia (30–40%) and mixed dementia (15–20%). Approximately 10–15% of direct costs in dementia are attributed to pharmacological treatment, and only 10–20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype–phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20–95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.

Key words  dementia – Alzheimer’s disease – APOE – CYP2D6 – pharmacogenetics – pharmacogenomics – multifactorial treatments


Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Edward C. Lauterbach; Jeff Victoroff; Kerry L. Coburn; Samuel D. Shillcutt; Suzanne M. Doonan; Mario F. Mendez


This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer’s and Parkinson’s diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

The most important detailed findings for each drug are briefly summarized in Table 1, Table 2, Table 3, and Table 4 (located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI). The recently discovered TDP-43 was also considered while this project was underway, but no relevant articles were evident for this protein.

It is evident from the above that there is significant variation in degree of investigation, cell lines studied, and methodological approaches. Other limitations include the varying use of neural tissues, variance in the neuronal types studied, use of neuroblastoma lines instead of neurons, study of immature or poorly differentiated cells that may be more prone to apoptosis than more mature cells, and the infrequent characterization of effects on αSyn, tau, and Aβ. Such deficiencies in the data significantly confound the ability to draw definitive conclusions. In particular, the deficiencies in the data raise the question as to the most valid, clinically relevant, and appropriate standards of evidence to apply in determining which preclinical findings will predictably translate into clinical neuroprotection in patients with neurodegenerative diseases.

A number of concerns impact the selection of an appropriate standard of evidence. First, there are no established general criteria for judging preclinical neuroprotective data across the diversity of neurodegenerative diseases. Second, unlike clinical evidence-based medicine (EBM) standards, there do not appear to be established uniform criteria for judging the diversity of preclinical findings. From an EBM perspective, the data considered here are even less compelling than Class II or IV18 or Level C19clinical case reports since they generally do not pertain to findings in human patients. Third, there are considerable variabilities across the present preclinical findings with respect to intra- and extramodel replication, replications in neural tissue, the specific neural tissues studied, and the specific brain locus even when neurons are consistently studied. These are summarized in Table 5. Fourth, replications are still needed using the same physiological dose range, particularly because some have observed bell—shaped rather than sigmoid—shaped neuroprotective dose—response curves.20,21 Fifth, some drugs have mixed actions, simultaneously possessing some neuroprotective actions and other neurodegenerative actions. It is not yet clear whether the various actions should receive equal weight or whether one may trump others (for example, effects on apoptotic measures may be more determinative in importance than effects on more “upstream” processes such as mitochondrial potential or proteasomal function). Sixth, there is no gold-standard preclinical model but, instead, a diversity of models that each have their own select benefits and limitations. These and other factors likely contribute to the current disconnect between preclinical findings and neuroprotective clinical trial results.

Some criteria for considering neuroprotective candidate agents have been elaborated in Parkinson’s disease22 and stroke.23 In Parkinson’s disease, scientific rationale, penetration of the blood-brain barrier, safety and tolerability, and efficacy in relevant animal models of the disease or an indication of benefit in human clinical studies constitute criteria.22 In the case of FDA-approved psychotropics reviewed here, which essentially meet most of these criteria (with the exception of systematic, consistent application in relevant neurodegenerative disease models), the question then becomes: how good is the available preclinical evidence of neuroprotection? Ravina et al.22 noted that the most problematic issue in Parkinson’s disease was evaluating animal data given the many different models that were of uncertain value in predicting results in humans and noted further that a clinical trial would actually be needed to demonstrate the predictive validity of any preclinical model. Similarly, it is not possible to judge the quality of the present preclinical findings by the models used because the predictive validities of the models remain unclear. In stroke,23 potentially successful drug candidates have been considered to be inferable from preclinical data by the following criteria: (a) adequately defined dose-response relations; (b) time window studies showing a benefit period; (c) adequate physiological monitoring in unbiased, replicated, randomized, blinded animal studies; (d) lesion volume and functional outcome measures determined acutely and at longer term followup; (e) demonstration in two animal species; (f) submission of findings to a peer-reviewed journal. However, even with these criteria, Gladstone et al.24 have pointed out that translation of preclinical findings to clinical efficacy has been hampered by a lack of functional outcomes, long-term end points, permanent ischemia models, extended time windows, and selective white matter evaluation in preclinical models whereas clinical studies are plagued by insensitive outcome measures, lack of stroke subtype specificity, and inattention to the ischemic penumbra, among other concerns. Ford25 has also pointed out that a number of compounds fulfilling these stroke neuroprotectant criteria have failed to afford translational clinical neuroprotection. Analogous concerns obtain for neurodegenerative disease preclinical models and clinical methods, particularly whether putative criteria will reliably predict translation to clinical neuroprotection. Additionally, a nearly endless array of clinical variables including gender, age, pharmacogenomics, medical history, coadministered drugs, and other factors may contribute to an inability to predict clinical neuroprotection despite preclinical success. Thus, predictive criteria remain in need of development.

Reflection upon these translational issues in regard to psychotropic neuroprotection in neurodegenerative diseases first suggests the need for replication within and between specific preclinical models in specific neurons at specific loci to elucidate physiological dose-response relations that should then themselves be replicated as a first step. Additionally, other issues seem relevant to the problem of determining which candidate drugs may be most likely to effect clinical neuroprotection. We suggest preliminary neuroprotective drug selection criteria for assessing the likelihood of translational clinical neuroprotection in neurodegenerative diseases (Table 6). These criteria, including preclinical (at least two replicated neuroprotective actions at physiological doses in an established neuroprotective model, neural tissue, and disease-specific animal model in excess of the number of known neurodegenerative actions) and clinical (delayed progression on clinical markers and unexpected benign disease course not accounted for by symptomatic properties) criteria, can be evaluated over time and modified as future data indicate. Given the lack of information regarding the utility of specific preclinical paradigms in predicting clinical neuroprotective effects, it is premature to rank or weight these criteria. Rather, recent concerns26 notwithstanding and until a better study methodology is developed, we suspect that the greater the number of criteria met by a candidate drug, the greater the likelihood of demonstrating translational clinical neuroprotective efficacy in a randomized, double-blind, placebo-controlled, delayed-start or randomized-withdrawal clinical trial.27 Such trials are needed because agents deemed promising based upon preclinical data often fail to demonstrate neuroprotection in clinical trials for reasons identified in the above paragraph. At present, preclinical demonstration of replicable neuroprotective effects in neural tissues at clinically-relevant doses does not assure a positive result in a clinical trial, nor does the absence of such evidence necessarily exclude clinical neuroprotective benefits. Until such clinical findings obtain, it is impossible to identify preclinical determinants predictive of translational clinical success and ascertain whether patients are actually being helped or harmed in a neuroprotective sense by the use of these drugs.

Beyond the methodological concerns expressed above, a practical assessment of these preclinical findings is still possible. Given the relative infancy of this field of research, the present state of the literature, the limitations of the data described above, and our current ignorance of preclinical evidence predictive of successful clinical translation, there is the very real possibility of prematurely disregarding findings that may ultimately prove to be of clinical significance with further research (a “type II” error) by applying an overly stringent standard of evidence. It seems that, at the present time, the proper approach is to instead look at the preponderance of the available findings and attempt some generalizations that constitute general impressions to be tested in future research, similar to the process of developing and refining clinical diagnostic criteria. Accordingly, the following observations are drawn from looking at all of the studies, without any exclusions, except where there are clearly contradictory data. As noted, many of the findings have not yet been independently replicated in the same model despite apparent replication in a different model (Table 5). Until the state of the literature develops to the point where independent replications in the same model are routinely observed, appropriate assessment criteria must be very liberal, resulting in conclusions that can only be viewed as preliminary. Adopting this approach with its attending caveats, some preliminary observations can be gleaned from the data. Below, we first consider drugs with respect to their neuroprotective potentials, distinguishing drugs meriting further study from those that have limitations dissuading further investigation and those for which too little data are available to form any conclusions. (We also summarize neuroprotective effects by drug class in Appendix 1 and drugs by neuroprotective actions in Appendix 2 [located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI%5D; Part 2 of this report focuses on the broader neuroprotective aspects of selected psychopharmacological classes.) Next, we assess the general properties of the various classes of psychotropics. We then consider each investigated cellular function with regard to the drugs that influence them. Finally, we detail a research agenda for drugs of interest and consider the progress made in clinical neuroprotective trials thus far, recommending a next step in their development.

Drugs of Neuroprotective Interest

Drugs meriting further study include:

  • pramipexole,
  • thioridazine,
  • risperidone,
  • olanzapine,
  • quetiapine,
  • lithium,
  • valproate,
  • nortriptyline,
  • desipramine,
  • maprotiline,
  • fluoxetine,
  • paroxetine,
  • buspirone,
  • clonazepam,
  • diphenhydramine, and
  • melatonin.

These are drugs with at least one significant neuroprotective action and relatively negligible countervailing neurodegeneration—promoting effects, as summarized in Table 1, Table 2, and Table 3 (especially the “Comments” column summarizing the data), and particularly Table 7 (tables located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI).

Drugs that are not recommended for further study at the present time due to more significant limiting issues (see Table 1, Table 2, and Table 3, especially “Comments” column summarizing the data). Haloperidol does not warrant further study because of tau hyperphosphorylation, reduced cell viability, and multiple proapoptotic actions, especially in hippocampus, cortex, striatum, and nigra. Fluphenazine, chlorpromazine, and clozapine, probably do not warrant further study because of multiple proapoptotic actions, and chlorpromazine inhibits tau dephosphorylation. Carbamazepine has variable neuroprotective properties. Oxcarbazepine promotes apoptosis. Clomipramine also generally promotes apoptosis. Diazepam has mixed effects on neural apoptosis, but uncouples oxidative phosphorylation, releases cytochrome c, and promotes apoptosis in a number of neuronal models, although it promoted ATP recovery and prevented cytochrome c release in a single study of ischemic hippocampal slices.

It should be emphasized that there are no convincing clinical data at present to indicate that these drugs are unsafe for clinical use due to neurodegenerative effects, only preclinical evidence to temper enthusiasm for clinical trial application as a neuroprotectant. Until such data become available, the use of these drugs continues to be guided by clinical symptomatic indications. The limiting actions described above are considered to be significant enough to likely detract from an overall neuroprotective effect, making positive findings less likely, hence our inability to recommend them at present. It must also be recognized that some of these limitations still await replication (Table 5), and that it is presently unknown precisely which neuroprotective modes of action are positively and negatively predictive of clinical neuroprotection.

Drugs for Which Limited Data Do Not Allow Recommendations

There are currently insufficient data for ropinirole, amantadine, thiothixene, aripiprazole, ziprasidone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, bupropion, sertraline, fluvoxamine, citalopram, trazodone, nefazodone, venlafaxine, duloxetine, mirtazapine, chlordiazepoxide, flurazepam, temazepam, chlorazepate, lorazepam, oxazepam, alprazolam, zolpidem, cyproheptadine, hydroxyzine, modafinil, ramelteon, benztropine, trihexyphenidyl, and biperiden.

Briefly, regarding the neuroprotective effects of psychopharmacological classes, certain generalizations are apparent (see Appendix 1 for details). There is some evidence to suggest that D2 agonists, lithium, some SSRIs, and melatonin reduce . D2 agonists, certain atypical antipsychotics and antidepressants, and melatonin suppress . Neuroleptics, lithium, certain heterocyclic antidepressants, the central benzodiazepine receptor agonist clonazepam, and melatonin inhibit . D2 agonists, atypical antipsychotics, lithium, antidepressants, the 5HT1a agonist buspirone, and melatonin inhibit , whereas the peripheral benzodiazepine receptor agonist diazepam promotes apoptosis. These, however, are gross generalizations, which are better explained in Appendix 1 and Appendix 2. Moreover, it is potentially erroneous to project neuroprotective effects upon a pharmacological class because neuroprotective properties may not relate to their currently recognized pharmacodynamic effects.

Above, we have indicated which drugs merit further study, those which cannot be recommended due to significant limiting issues, and those with inadequate data to allow assessment. Among drugs meriting further study, Table 8 discloses the various agents along with evidential weights for their various neuroprotective actions. It can be seen that drugs that inhibit apoptosis and have at least one other general antiapoptotic action (each demonstrated by a net of two or more studies supporting a neuroprotective action, without consideration of their effects on specific proteins) include pramipexole, olanzapine, lithium, desipramine, and melatonin. The remaining agents have less robust findings supporting general neuroprotective actions. Considering the effects of these drugs on proteins and at least one other neuroprotective action in a disease-specific model, the most promising drugs in Alzheimer’s disease would include olanzapine, lithium, and melatonin while drugs with less robust support in Alzheimer’s disease include pramipexole, quetiapine, valproate, and desipramine. Applying the same criteria, drugs of promise in Parkinson’s disease include pramipexole and melatonin, while drugs with less robust support in Parkinson’s disease include olanzapine, lithium, valproate, desipramine and clonazepam. Similarly, in Huntington’s disease, desipramine is the most promising, with less robust support for lithium, valproate, nortriptyline, and maprotiline. There is some support for pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis. However, as we have pointed out above, it is premature to draw any clinical conclusions from these data because of the limitations we have described and because more data will be forthcoming.

Directions for Future Research

Given this inability to draw clinical conclusions, we provide the next steps that should be undertaken in developing psychotropic research to the point that results can guide the clinical application of these drugs for neuroprotection. While it is not clear what the most predictive models of clinical neuroprotection are, and what the most important neuroprotective mechanisms are, it is apparent that some drugs are further along in their preclinical research than others. It is also clear that some seemingly paradoxical neuroprotective outcomes are seen, such as modafinil’s ability to increase glutamate release and yet reduce glutamate toxicity, and paroxetine’s ability to reduce hippocampal Aβ production in Alzheimer’s disease transgenic mice despite its anticholinergic properties that would otherwise tend to increase Aβ production. These seeming contradictions point to the need to focus on research findings rather than our current limited theoretical understanding. Thus, we outline the next research steps to be taken to elaborate findings that will move us toward establishing neuroprotective drugs that can be applied by clinicians.

Apathy Treatments

It would be of interest to investigate pramipexole in normal neurons, especially dopaminergic and cholinergic neurons.

Pramipexole should be better characterized as to its effects on αSyn, Aβ, tau, and Aβ fibril and oligomer-induced reactive oxygen species formation as well as on the proteasome and on mitochondrial metabolism. It then should be investigated in clinical neuroprotection paradigms in neurodegenerative disease, particularly Parkinson’s disease.

The next step for amantadine involves investigations in neurons.


Risperidone needs more study to determine its neuroprotective potential. Its ability to reduce Complex I activity in regions of the brain, albeit not in the midbrain, indicates the need for further research as to its long-term safety in neurodegenerative diseases affecting the hippocampus, frontal lobe, and striatum, including Alzheimer’s disease, frontotemporal lobar degeneration, and Huntington’s disease. Clinical effects tend to contraindicate its use in Parkinson’s disease.

Although olanzapine should be better characterized as to its multiple neuroprotective effects (especially on the proteasome and mitochondrial permeability transition pore development), antimuscarinic and parkinsonian clinical properties argue against its application in Alzheimer’s disease and Parkinson’s disease.

Quetiapine should be better characterized as to its effects on αSyn, Aβ, tau, the proteasome, and protection against rotenone toxicity. Further studies using Aβ and initial studies using MPP+ should be carried out, with subsequent disease-modification studies in Alzheimer’s disease and Parkinson’s disease if the preceding studies indicate safety, although antihistaminic and anticholinergic clinical properties can constitute a limitation to use in Alzheimer’s disease.

Trifluoperazine, chlorpromazine, and thioridazine might be further studied in situations where inhibition of mitochondrial permeability transition pore development is of utility.

Aripiprazole and ziprasidone should be studied for their neuroprotective properties, given their low proclivities to induce extrapyramidal side effects in people with neurodegenerative disease.

Mood Stabilizers

Lithium should be studied for neuroprotection in patients with Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and cerebral ischemia. A clinical trial in Alzheimer’s disease is currently under way.

Investigation of valproate’s ability to induce mitochondrial permeability transition pore development but not mitochondrial membrane depolarization or cytochrome c release may yield information that may help develop neuroprotective mitochondrial strategies.

Valproate might be investigated in patients with Parkinson’s disease and oncological diseases for its antiapoptotic effects in the former and proapoptotic effects in microglia and the latter. Valproate’s ability to increase αSyn concentrations may be either beneficial or detrimental in Parkinson’s disease and other synucleinopathies, and further research is needed. Activated microglia appear to be of importance in neurodegenerative diseases, especially Alzheimer’s disease. Results of a recent clinical trial in Alzheimer’s disease are not yet available.


Desipramine, nortriptyline, and maprotiline should be studied in other models of Huntington’s disease. If effective, they might be tried in other neurodegenerative disease models and in depressed patients with Huntington’s disease. Nortriptyline’s effects in Huntington’s disease yeast and amyotrophic lateral sclerosis mouse models deserve replication.

Fluoxetine has inhibited neural stem cell apoptosis, hippocampal apoptosis in newborn mice and rats and serotonin-induced apoptosis. Although it has some proapoptotic properties, fluoxetine should be studied further as a neuroprotectant in Alzheimer’s disease.

Paroxetine should be studied further for neuroprotective properties, especially in regard to reductions in Aβ and hyperphosphorylated tau.

Anxiolytics and Hypnotics

Buspirone has inhibited apoptosis in several neuronal models and now deserves study in regard to other related characteristics. If further studies indicate safety, studies in patients with neurodegenerative disease should then be undertaken.

Which types of GABA-A agonists protect against Aβ neurotoxicity and which do not requires clarification.

Clonazepam should be studied further for its restorative properties in Complex I deficiency, and should be better characterized in regard to apoptotic effects in neuronal models, especially on frontal lobe apoptosis in mature animals. If favorable results are forthcoming, it might then be tried in patients with neurodegenerative disease, especially Parkinson’s disease, although its association with falls in the elderly is a limitation.

Diphenhydramine should be further characterized in inflammatory, malignant, hypoxic, and other models where histamine plays a role.

Melatonin might now be investigated in patients with Alzheimer’s disease and in those with Parkinson’s disease.

Comprehensive Strategies

Deficiencies detailed in Table 5 deserve to be addressed in future studies. Validation of Table 6 translational predictive criteria awaits investigation. The relative predictive weightings of the various criteria also await outcome studies.

Combination therapies of psychotropics with differing profiles of neuroprotective actions may yield greater clinical impact than monotherapies. These varying profiles are depicted in Table 8. For example, across neurodegenerative diseases, the combination of lithium and melatonin might provide neuroprotective synergies, as might pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis, lithium, and desipramine in Huntington’s disease, and pramipexole, lithium, desipramine, and melatonin in Alzheimer’s disease (Table 8). In Alzheimer’s disease, lithium and melatonin together might synergize efficacy at Aβ, hyperphosphorylated tau, reactive oxygen species, transition pore development, and apoptosis, with lithium perhaps improving ubiquitylation. In Parkinson’s disease, this combination plus pramipexole may synergize benefits to reactive oxygen species, transition pore, and apoptosis, with lithium perhaps improving ubiquitylation and pramipexole and melatonin perhaps synergizing efficacy on αSyn. It should be remembered, however, that some combination therapies, applied in cancer chemotherapy, have sometimes resulted in a reduced efficacy of all drugs and an increase in side-effects.28 Animal trials of proposed combinations would be a first step in evaluating their safety and efficacy.

Progress Thus Far: Clinical Trials

So far, some preliminary progress has been made in identifying the clinical neuroprotective properties of some of these agents. A search performed on October 9, 2007 using the search terms “randomized clinical trial AND (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) for each drug revealed only one clinical neuroprotection study (ropinirole versus -dopa), and two studies evaluating glutathione reductase and a gamma interferon, relevant to disease progression, but without evaluating actual indices of clinical neuroprotection. A 6-18F-fluorodopa PET study of 186 patients with Parkinson’s disease randomized to either ropinirole or -dopa revealed a significant one third reduction in the rate of loss of dopamine terminals in subjects treated with ropinirole.29 A study of valproate plus placebo versus valproate plus melatonin in patients with epilepsy demonstrated a significant increase in glutathione reductase in the melatonin group, but no clinical indices of actual neuroprotection were evaluated in that study.30 A study in patients with relapsing-remitting multiple sclerosis identified a relationship between sertraline treatment of depression and attenuation of proinflammatory cytokine IFN-gamma, but again, actual indices of clinical neuroprotection were not assessed.31 In addition to the findings of the search, the CALM-Parkinson’s disease study involving the dopamine agonist pramipexole in Parkinson’s disease found faster progression (or at least less improvement on total UPDRS score) but slower dopamine transporter signal loss than with -dopa over 46 months,32 although the study has been criticized for lack of a placebo, group heterogeneity, and confounding influences on dopamine transporters. In contrast, a 2-year study of ropinirole found no significant difference in fluorodopa uptake compared to -dopa treatment (−13% versus −18%).33

A search of clinical trials (www.clinicaltrials.gov) on October 9, 2007 using the terms (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) and neurodegenerative diseases revealed only a few studies in progress. These included pramipexole in amyotrophic lateral sclerosis, early versus delayed pramipexole in Parkinson’s disease, and valproate in spinal muscular atrophy. Since that time, as of February 1, 2009, additional studies have been registered. In Alzheimer’s disease, these include a short-term study of CSF tau epitopes with lithium, brain volume and clinical progression with valproate, and hippocampal volume, brain volume, and clinical progression with escitalopram. In frontotemporal dementia, there is a single study of CSF and brain volume with quetiapine versus D-amphetamine. In Huntington’s disease, there is a study of CSF BDNF levels with lithium versus valproate. In dementia with Lewy bodies and Parkinson’s disease dementia (PDD), there is a study of clinical progression with ramelteon. In Parkinson’s disease, there is a study of striatal dopamine transporter by β-CIT SPECT with pramipexole versus -dopa while an 8 year study of disability with pramipexole has been terminated. Only the spinal muscular atrophy and dementia with Lewy bodies/PDD studies employ clinical neuroprotective designs (delayed-start paradigm), and the validity of biomarker correlates, particularly dopamine transporter measures in Parkinson’s disease, continues to be studied.

The discussion above relies on multiple investigative approaches using a number of different psychotropics in a variety of models and a diversity of cell lines. A major caveat is that preclinical results do not necessarily translate into clinical realities. For example, favorable preclinical findings for the neuroprotectant minocycline exist in Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, stroke, spinal cord injury, and MS models, but a recent phase III trial in patients with amyotrophic lateral sclerosis was halted because of a 25% faster rate of neurological progression with the active drug than with placebo.34 Nevertheless, some generalizations seem possible at this stage. The considerations above are offered in hopes of stimulating the identification and development of pharmaceuticals that are useful both for symptomatic improvement and for long-term neuroprotection in neurodegenerative disease. Pursuit of the directions for research suggested above may contribute to that development.


Read Full Post »

Older Posts »