Feeds:
Posts
Comments

Posts Tagged ‘University of Pennsylvania’


The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD.

 

From CNN at https://www.cnn.com/2020/06/27/health/coronavirus-treatment-fajgenbaum-drug-review-scn-wellness/index.html

Updated 8:17 AM ET, Sat June 27, 2020

(CNN)Every morning, Dr. David Fajgenbaum takes three life-saving pills. He wakes up his 21-month-old daughter Amelia to help feed her. He usually grabs some Greek yogurt to eat quickly before sitting down in his home office. Then he spends most of the next 14 hours leading dozens of fellow researchers and volunteers in a systematic review of all the drugs that physicians and researchers have used so far to treat Covid-19. His team has already pored over more than 8,000 papers on how to treat coronavirus patients.

The 35-year-old associate professor at the University of Pennsylvania Perelman School of Medicine leads the school’s Center for Cytokine Storm Treatment & Laboratory. For the last few years, he has dedicated his life to studying Castleman disease, a rare condition that nearly claimed his life. Against epic odds, he found a drug that saved his own life six years ago, by creating a collaborative method for organizing medical research that could be applicable to thousands of human diseases. But after seeing how the same types of flares of immune-signaling cells, called cytokine storms, kill both Castleman and Covid-19 patients alike, his lab has devoted nearly all of its resources to aiding doctors fighting the pandemic.

A global repository for Covid-19 treatment data

Researchers working with his lab have reviewed published data on more than 150 drugs doctors around the world have to treat nearly 50,000 patients diagnosed with Covid-19. They’ve made their analysis public in a database called the Covid-19 Registry of Off-label & New Agents (or CORONA for short).
It’s a central repository of all available data in scientific journals on all the therapies used so far to curb the pandemic. This information can help doctors treat patients and tell researchers how to build clinical trials.The team’s process resembles that of the coordination Fajgenbaum used as a medical student to discover that he could repurpose Sirolimus, an immunosuppressant drug approved for kidney transplant patients, to prevent his body from producing deadly flares of immune-signaling cells called cytokines.The 13 members of Fajgenbaum’s lab recruited dozens of other scientific colleagues to join their coronavirus effort. And what this group is finding has ramifications for scientists globally.
This effort by Dr. Fajgenbaum’s lab and the resultant collaborative effort shows the power and speed at which a coordinated open science effort can achieve goals. Below is the description of the phased efforts planned and completed from the CORONA website.

CORONA (COvid19 Registry of Off-label & New Agents)

Drug Repurposing for COVID-19

Our overarching vision:  A world where data on all treatments that have been used against COVID19 are maintained in a central repository and analyzed so that physicians currently treating COVID19 patients know what treatments are most likely to help their patients and so that clinical trials can be appropriately prioritized.

 

Phase 1: COMPLETED

Our team reviewed 2500+ papers & extracted data on over 9,000 COVID19 patients. We found 115 repurposed drugs that have been used to treat COVID19 patients and analyzed data on which ones seem most promising for clinical trials. This data is open source and can be used by physicians to treat patients and prioritize drugs for trials. The CDCN will keep this database updated as a resource for this global fight. Repurposed drugs give us the best chance to help COVID19 as quickly as possible! As disease hunters who have identified and repurposed drugs for Castleman disease, we’re applying our ChasingMyCure approach to COVID19.

Read our systematic literature review published in Infectious Diseases and Therapy at the following link: Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

From Fajgenbaum, D.C., Khor, J.S., Gorzewski, A. et al. Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review. Infect Dis Ther (2020). https://doi.org/10.1007/s40121-020-00303-8

The following is the Abstract and link to the metastudy.  This study was a systematic review of literature with strict inclusion criteria.  Data was curated from these published studies and a total of 9152 patients were evaluated for treatment regimens for COVID19 complications and clinical response was curated for therapies in these curated studies.  Main insights from this study were as follows:

Key Summary Points

Why carry out this study?
  • Data on drugs that have been used to treat COVID-19 worldwide are currently spread throughout disparate publications.
  • We performed a systematic review of the literature to identify drugs that have been tried in COVID-19 patients and to explore clinically meaningful response time.
What was learned from the study?
  • We identified 115 uniquely referenced treatments administered to COVID-19 patients. Antivirals were the most frequently administered class; combination lopinavir/ritonavir was the most frequently used treatment.
  • This study presents the latest status of off-label and experimental treatments for COVID-19. Studies such as this are important for all diseases, especially those that do not currently have definitive evidence from randomized controlled trials or approved therapies.

Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review

Abstract

The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA. Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Read the Press Release from PennMedicine at the following link: PennMedicine Press Release

Phase 2: Continue to update CORONA

Our team continues to work diligently to maintain an updated listing of all treatments reported to be used in COVID19 patients from papers in PubMed. We are also re-analyzing publicly available COVID19 single cell transcriptomic data alongside our iMCD data to search for novel insights and therapeutic targets.

You can visit the following link to access a database viewer built and managed by Matt Chadsey, owner of Nonlinear Ventures.

If you are a physician treating COVID19 patients, please visit the FDA’s CURE ID app to report de-identified information about drugs you’ve used to treat COVID19 in just a couple minutes.

For more information on COVID19 on this Open Access Journal please see our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

Read Full Post »


 

From Technicall.y Philly.com

Reporter: Stephen J. Williams, PhD

Spark Therapeutics’ $4.8B deal confirmed as biggest-ever VC-backed exit in Philly

Quick update on this week’s news: The University City life sciences company’s acquisition by Swiss pharma giant Roche is the biggest acquisition ever of a VC-backed company within city limits, per PitchBook and PACT.

The eye-popping $4.8 billion sticker price on Spark Therapeutics’acquisition deal with Roche announced on Monday is shaping up to be the largest exit ever within city limits for a venture-backed company, according to data from financial data provider PitchBook and the Philadelphia Alliance for Capital and Technologies (PACT).

“Filtering down to just Philadelphia proper does reveal that Spark Therapeutics, once the deal closes, will be the biggest exit ever for Philly-based venture-backed exits,” the company said in an email, citing data from an upcoming report.

According to the Seattle-based company’s data, the current holder of the largest Philly-proper exit title goes to Avid Radiopharmaceuticals, which in 2010 announced its acquisition by Lilly in a deal valued at up to $800 million.

Founded in 2013, Spark is a publicly traded spinout of Children’s Hospital of Philadelphia (CHOP), which invested $33 million in the company. The Philadelphia Inquirer reports that CHOP stands to reap a total return of $430 million for its minority stake in Spark Therapeutics.

As part of the acquisition deal, the company will remain based out of 3711 Market St., and continue to do business as a standalone Roche company.

“This transaction demonstrates the enormous value that global biotech companies like Roche see in gene therapy, a field in which Philadelphia is the unquestioned leader,” said Saul Behar, senior VP of  advancement and strategic initiatives at the University City Science Center, the West Philly research park where Spark began and grew its operations. “[This] further validates Greater Philadelphia’s status as a biotech hub with a very bright future.”

Spark CEO Jeff Marrazzo said the deep pool of resources from Roche, the company plans to “accelerate the development of more gene therapies for more patients for more diseases and further expedite our vision of a world where no life is limited by genetic disease.”

Other articles on Gene Therapy and Retinal Disease on this Open Access Online Journal include:

Women Leaders in Cell and Gene Therapy

AGTC (AGTC) , An adenoviral gene therapy startup, expands in Florida with help from $1 billion deal with Biogen

Artificial Vision: Cornell and Stanford Researchers crack Retinal Code

D-Eye: a smartphone-based retinal imaging system

 

 

Read Full Post »


AACR and Philly New Media Present a Town Hall Discussion on Precision Medicine

Cancer Precision Medicine: Big Ideas in Research, Treatment, and Prevention

A Town Hall Forum will discuss the latest findings with regard to precision medicine, its impact currently in cancer treatment, and future directions, discussed by some of the preeminent cancer researchers and oncologists in the country. This unprecedented event is being hosted by the American Association for Cancer Research (AACR) and Philadelphia Media Network – publisher of The Philadelphia Inquirer, Daily News, and Philly.com.

Given the following speakers, this event will have a large focus on use of cancer immunotherapy as well as new targets in the precision medicine arena.

Register today: Philly.com/CancerEvent – Use the promo code “AACR” for discounted $45 tickets.

When: Thursday, January 21, 2016 • Program: 2 pm • Networking reception: 5:30 pm.

Where:  The College of Physicians of Philadelphia • 19 South 22nd Street, Philadelphia, Pa.

The event will be held in Philadelphia at the College of Physicians of Philadelphia, home of the famous Mutter Museum.

Please follow the meeting coverage on @pharma_BI and using the following @ handle and # hastags of Twitter:

@AACR

@pharma_BI

@PhillyInquirer

#cbi16

#precisionmedicine

#endcancer

 

From Penn Medicine News Blog: Archives (please click on link below)

Penn’s Center for Personalized Diagnostics (CPD), which recently named Kojo S.J. Elenitoba-Johnson, MD, as its founding director, is diving deeper into cancer patients’ tumors with next generation DNA sequencing.

The genetic tests help refine diagnoses with greater precision than standard imaging tests and blood work by spotting known mutations that can inform the treatment plan. Since it launched in February 2013, the CPD has performed more than 4,000 advanced diagnostics, representing a wide range of cancers.  It’s also producing actionable findings: Of those tests, 75 percent found disease-associated mutations, revealing possible new treatment pathways.

This new CPD video helps breakdown how the process works, but a patient story can really help connect the dots. We’ve written about several people who benefited from the CPD, including one acute myeloid leukemia patient with an FLT3 mutation that made her a candidate for a targeted therapy, and another whose cholangiocarcinoma was successfully treated with a BRAF-targeted therapy after the mutation—typically associated with melanoma—was spotted.

ACC’s role as a national leader in personalized cancer care was also reinforced with the opening of the Center for Rare Cancers and Personalized Therapy in 2015.

Directed by Marcia Brose, MD, PhD, this virtual center enrolls patients into clinical trials based on genetic markers rather than tumor origin.  Patients with the same mutation, BRAF for instance, but different cancers, are part of the same clinical study investigating a targeted therapy.  A story, set to air on TV news affiliates across the country in the upcoming weeks, will feature a patient with a rare salivary tumor who ran out of treatment options, until a HRAS mutation identified through the CPD put him back on track, after switching to the drug tipifarnib. The patient responded well, and a recent scan revealed that his disease has stabilized.

“Philadelphia is a hotbed for healthcare innovation and groundbreaking scientific research—which becomes even more apparent as the ACC continues to move the needle in the precision medicine world,”Abramson Cancer Center (ACC) director Chi Van Dang, MD, PhD, said.  “Quickly evolving diagnostics and genetic tests, cancer vaccines, and powerful personalized therapies that use the body’s own immune system to fight off cancer: These are just a few of the medical advances being utilized today that are giving patients the greatest chance.”

For Media Inquiries see the following AACR contact information:

Julia Gunther
Assistant Director, Media and Public Relations
215-446-6896
Cell: 267-250-5441
Fax: 215-861-5937
julia.gunther@aacr.org
Gunther promotes the AACR’s meetings, journals, and initiatives to the media and the public.

Lauren Walens
Senior Manager, Media and Public Relations
215-446-7163
Fax: 267-765-1050
lauren.walens@aacr.org
Walens promotes the AACR’s meetings, journals, and initiatives to the media and the public. She also manages the AACR’s blog, Cancer Research Catalyst.

Lauren Riley
Senior Coordinator, Media and Public Relations
215-446-7155
Fax: 215-446-7291
lauren.riley@aacr.org
Riley is responsible for media relations promotion and support, conference newsroom logistics, writing and proofreading, website and news release copy, as well as office support for the Communications and Public Relations Department staff.

 

 

 

Read Full Post »


 

Leaders in the CAR-T Field Are Proceeding With Cautious Hope

Reporter: Stephen J. Williams, Ph.D.

It wasn’t a long time ago, in fact the May 26, 2014 Cover Story in Forbes entitled “Is This How We’ll Cure Cancer” with cover photo of Novartis CEO Joseph Jimenez and subtitle “Will This man Cure Cancer?” highlighted the promise of CAR-T therapy as the ‘magic bullet’ therapy which will eventually cure all cancer. However, over the years, the pioneers of such therapy, while offering impressive clinical results, caution not to get to eager in calling CAR-T as the end-all-be-all cure but insist there are many issues that need be resolved.

The Allogenic Approach

In an interview for LabBiotech.eu Phillip Hemme had a discussion (and wonderful writeup) with André Choulika, the CEO of the French CAR-T miracle Cellectis on the current state of CAR-T therapy for cancer. Below is the interview in full as ther ae multiple important point Dr. Choulika mentioned, including how much is needed to be done in the field.

Cellectis’ CEO: “I’m just trying to be realistic, CAR-T is not THE miracle cure for Cancer”

 

 

Cellectis

CAR-T is solidifying in everybody’s mind as the next revolution in Cancer treatment. But there is still a lot to do…That’s basically what came out from my discussion with André Choulika, the CEO of the French CAR-T miracle Cellectis.

Cellectis is probably the most successful Biotech in France. It was founded in 1999 by Choulika himself (not alone though), following the discovery of meganucleases ability to change gene editing. Today, Cellectis is a well-known Biotech company counting over 100 employees end of October and having a market cap north of 1 Billion euros.

The company is now focused on the development of allogenic CAR-T (from generic donors  – i.e. not from the patient themself). With these universal CAR-T candidates (UCARTs). Cellectis has signed a massive partnership with the French pharma Servier, as well as Pfizer (which owns 8% of Cellectis), and has just announced two big milestones for the company within the last few weeks.

It is now able to produce it’s allogenic CAR-T in a GMP settings and it releases results from the “miracle” treatment of a 11-month old girl from the UK with multi-resistant leukemia.

 

Let’s start directly with the latest news…People seemed over-enthusiastic about UCART19…even the New York Times wrote about it. What do you think?

It’s a great news for Cellectis even though it’s still a very early result, in a single patient only. What’s important for us is that the first human patient received our treatment without showing any adverse effects (such as no cytokinetic storm) and our CAR-T cells were still active in the body 3 months after the injections.

Now, we have to expand the clinical trials to several patients and showing data from a cohort of patients. We are now on track to file the clinical trial application by the end of the year.

Your approach in the CAR-T is pretty unique. You are using donor’s cells to treat many different patients, whereas most CAR-T approaches are autologous (i.e. engineered the patient’s own cells).  Is the future in CAR-T the allogenic approach alone?

When we started to move into the CAR-T field we were pretty reluctant because there are not many examples of commercial success in the field yet. But CAR-T has still attracted many big players such as Novartis, Celgene, Juno or Kite. These each have a strong involvement in making autologous therapies work commercially (Celgene especially, which makes most of its revenue from groundbreaking and pricey cancer drugs).

On our side, we want to make this therapy accessible to a larger population and have good market access at the end. We have already pretty good reason to think it could work out well for us. We’ll see though…

Comment: Reuters published a report a few weeks ago estimating the cost of autologous CAR-T could be above $450K per treatment, which would make it economically not realistic for the healthcare payers.

CAR-T seems to be extremely hype right now. At BIO-Europe 2015, I had the impression everybody was talking about CAR-T. Do you think it could have the same impact as monoclonal antibodies?

What’s interesting with CAR-T is that you can target cells which expresses less receptors (10k receptors instead of 100k for monoclonal antibodies). This increases the targets for CAR-T and the possibilities linked.

But there are also downsides. Tissues with low expressions can become targets too and CAR-T cells would start attacking healthy cells.

People should not overemphasise CAR-T. We are still at the beginning of the beginning of this technology. And it will probably have to be combined with surgery or checkpoint inhibitors.

 

You seem pessimistic about CAR-T…?

I am just trying to be more realistic, even though I am super positive about the technology. It will bring something really great to Haematology field, but is not a cure for Cancer. It’s more of a long-haul race in the right direction as opposed to fast results, and we expect great things perhaps 20 years down the line as opposed to 2016.

But yes, it will probably not be the miracle product some people are talking about.

As for every early technology, there are many challenges associated with its development. What are the main ones worth discussing?

I would say you have four main challenges…

The administration of the cells will be challenging. We have to find way of injecting repeated doses of the product (to ensure the therapy is fully effective seeing as CAR-T cells have a limited lifespan). This is difficult because of immunogenicty against the therapy.

Secondly, combination will play an essential role too and checkpoint inhibitors should be involved.

The last two are linked to the targets.

As I mentioned before, CAR-T can be too sensitive and one way to control that would be to induce “logic gates” where the cells would only act if a combination of receptors would be present. The last challenge is to find other antigens.

Most of the CAR-T cells today target the same antigen: CD19+. We should find new antigens and many companies are on the track, including us.

 

CD19 CART

An anti-CD19 CAR-expressing T cell recognizing a CD19+ (Source: Kochenderfer et al., Nature Reviews Clinical Oncology 10, 267-276, doi: 10.1038/nrclinonc.2013.46)

Autologous CART therapy

Dr. Carl June of University of Pennsylvania, who has helped pioneer the field of CAR-T therapy for leukemia, has also been cautiously hopeful on the progress of the therapy. In his 2015 AACR National Meeting address, he highlighted some achievements they had with CAR-T therapy in both hematologic as well as solid tumors however it was stressed that there is much work to do with regards to optimization of the system, characterization of new tumor antigens for diverse tumor types, as well as the need to develop optimal treatment strategies to mitigate toxicities. Indeed many of the pioneers in the field have been proactive in helping to develop pharmacovigilance, safety, and regulatory strategies (highlighted in a post found here: NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee and mitigating toxicities in a post Steroids, Inflammation, and CAR-T Therapy) and much credit should be given to these researchers.

https://youtu.be/1sA_oz_1P5E

Cancer Research Institute’s Breakthroughs in Cancer Immunotherapy Webinar Series are offered free to the public and feature informative updates from leaders in cancer immunotherapy, followed by a moderated Q&A. On June 10, 2013, Carl H. June, M.D., a specialist in T cell biology and lymphocyte activation at the Perelman School of Medicine, University of Pennsylvania, discussed his groundbreaking work that has led to remarkable remissions of advanced cancer. He focused on recent and ongoing successes in developing treatments with T cells that have been genetically engineered to target cancer. Called chimeric antigen receptor T cells (CAR T cells), these modified immune cells have proven effective at eliminating cancer in some patients, and offer great hope for this emerging strategy in cancer immunotherapy. For more information on this webinar, or to register for upcoming webinars, please visit www.cancerresearch.org/webinars.

Below are reports from the 2015 American Society of Hematology Conference by Novartis on results from CTL109 CART therapy trials. One trial is on response rate in B-cell lymphomas and follicular cell lymphomas while the second report is ongoing trial results in childhood refractory ALL, both conducted at University of Pennsylvania.

Novartis presents response rate data for CART therapy CTL019 in lymphoma

(Ref: Global Post, NASDAQ, PR Newswire)

posted on FirstWorldPharma.com December 6th, 2015

By: Matthew Dennis

Novartis announced Sunday data from an ongoing Phase IIa study demonstrating that the experimental chimaeric antigen receptor T-cell (CART) therapy CTL019 led to an overall response rate (ORR) at three months of 47 percent in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and an ORR of 73 percent in adults with follicular lymphoma. The results of the trial were presented at the American Society of Hematology annual meeting.

Findings from the study, which was conducted by the University of Pennsylvania’s Perelman School of Medicine, include 15 adults with DLBCL and 11 with follicular lymphoma who were evaluable for response. Results showed that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with follicular lymphoma who achieved a PR at three months converted to CR by six months.

Novartis added that one DLBCL patient with a PR at three months experienced disease progression at six months after treatment. Further, one follicular lymphoma patient with a PR at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. The company indicated that median progression-free survival was 11.9 months for patients with follicular lymphoma and 3 months for those with DLBCL.

In the study, four patients developed cytokine release syndrome (CRS) of grade 3 or higher. Novartis noted that during CRS, patients typically experience varying degrees of influenza-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. Meanwhile, neurologic toxicity occurred in two patients in the trial, including one grade three episode of delirium and one possibly related grade five encephalopathy.

“These data add to the growing body of clinical evidence on CTL019 and illustrate its potential benefit in the treatment of relapsed and refractory non-Hodgkin lymphoma,” commented lead investigator Stephen Schuster. Novartis indicated that the findings keep CTL019 on track for submission to the FDA in 2017. Usman Azam, global head of Novartis’ cell and gene therapies unit, said “we remain consistent again with the data set.”

“It’s an attractive population, it’s a population that continues to have a huge unmet need, it’s a cornerstone of our investments,” Azam remarked. Analysts expect CART therapies, once approved, to cost up to $450 000 per patient. Novartis acknowledged that prices will be high, but declined to give further details. “With any disruptive innovation that comes, initially, cost of goods is very challenging,” Azam said, adding “as time goes on, and more patients are treated, we will simplify that cost base.”

Source: http://www.firstwordpharma.com/node/1338217?tsid=28&region_id=2#axzz3tfDVaT1f

 

 

Novartis AG (NVS)’s Experimental Therapy Wipes Out Blood Cancer in 93 Percent of Patients

Reported in Biospace.com (for full article see here)

Novaritis and University of Pennsylvania reported results of the CTL019 CART trials for the treatment of children with relapsed/refractory acute lymphoblastic leukemia at the 2015 Annual Hemotologic Society Meeting. 55 of 59 patients, or 93 percent, experienced complete remissions with CTL019. The study did show that at the end of one year, 55 percent of patients had a remission-free survival rate and that 18 patients continued to show complete remission following one year

 

Other posts on the Open Access Journal on CAR-T therapy include

 

CAR-T therapy in leukemia

Steroids, Inflammation, and CAR-T Therapy

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

 

Read Full Post »


Common Heart Failure: Clinical Considerations of Heritable Factors

Reporter: Aviva Lev-Ari, PhD, RN

 

Clinical Considerations of Heritable Factors in Common Heart Failure

Thomas P. Cappola, MD, ScM and Gerald W. Dorn II, MD

Author Affiliations

From the Department of Medicine, University of Pennsylvania, Philadelphia, PA (T.P.C.), and Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO (G.W.D.II.).

Correspondence to Gerald W. Dorn II, MD, Center for Pharmacogenomics, Washington University, 660 S Euclid Ave, Campus Box 8220, St Louis, MO 63110. E-mail gdorn@dom.wustl.edu

Introduction

Heart failure is a common condition responsible for at least 290 000 deaths each year in the United States alone.1 A small minority of heart failure cases are attributed to Mendelian or familial cardiomyopathies. The majority of systolic heart failure cases are not familial but represent the end result of 1 or many conditions that primarily injure the myocardium sufficiently to diminish cardiac output in the absence of compensatory mechanisms. Paradoxically, because they also injure the myocardium, it is the chronic actions of the compensatory mechanisms that in many instances contribute to the progression from simple cardiac injury to dilated cardiomyopathy and overt heart failure. Thus, the epidemiology of common heart failure appears to be just as sporadic as its major antecedent conditions (atherosclerosis, diabetes, hypertension, and viral myocarditis).

Familial trends in preclinical cardiac remodeling2 and risk of developing heart failure3reveal an important role for genetic modifiers in addition to clinical and environmental factors. Candidate gene studies performed over the past 10 years have identified a few polymorphic gene variants that modify risk or progression of common heart failure.4 Whole-genome sequencing will lead to the discovery of other genetic modifiers that were not candidates.5 The imminent availability of individual whole-genome sequences at a cost competitive with available genetic tests for familial cardiomyopathy will no doubt further expand the list of putative genetic heart failure modifiers. Heart failure risk alleles along with traditional clinical factors will need to be considered by clinical cardiologists in their design of optimal disease surveillance and prevention programs and in individually tailoring heart failure management.

The use of individual genetic make-up is likely to have the earliest and greatest impact on managing patients with heart failure by tailoring available pharmacotherapeutics to optimize patient response and minimize adverse effects (ie, the area of pharmacogenetics). Modern heart failure management has been derived and directed by the results of large, randomized, multicenter clinical trials. When standard therapies are applied according to the selection criteria used in these trials, they prolong average survival across affected populations or decrease the incidence of heart failure in populations at risk.6 For this reason, standardized treatment guidelines prescribe heart failure therapies according to trial designs, aiming for the same target doses and general treatment approaches,7 and largely ignore individual characteristics. In this article, we review established and emerging knowledge of genetic influence on common heart failure and try to anticipate how these genetic factors may be best used to eschew the cookie-cutter approach to heart failure management and move toward implementing a personalized medicine approach for the treatment and prevention of this important and prevalent disease.

The Concept of Genotype-Directed Personal Medical Management in Heart Failure

Variation in clinical heart failure progression and therapeutic response (either benefits or side effects) supports the need for a more individualized approach to disease management. On the basis of clinical stratification (eg, by etiology of heart failure as ischemic versus nonischemic, functional status, comorbid disease), physicians try to match each patient’s specific heart failure syndrome with a therapeutic regime devised to provide the most benefit. Standard heart failure pharmacotherapy currently comprises a minimum of 3 medications (angiotensin-converting enzyme [ACE] inhibitors, β-blockers, and aldosterone antagonists), with consideration of additional medications (hydralazine/isosorbide, angiotensin receptor blockers) and diuretics. The recommended target dosages for these agents, derived from their respective clinical trials, is rarely achieved,8 partly because of untoward clinical side effects such as low blood pressure or renal dysfunction. Accordingly, the published guidelines most often are applied in each individual patient using ad hoc approaches derived from personal experience and the “art of medicine.”

Technological advances in human genomics promise a different approach and are bringing cardiology into an era of clinically applied pharmacogenetics9 (whether we want to or not). As sequencing costs decline, it is not hard to envision that patients will present having had their entire genome already sequenced. The imperative to apply genome information in clinical settings will increase, as demonstrated by recent proof-of-concept studies.10 Our field seems poorly prepared for this type of evolution in care; Roden et al9 identified 3 major barriers: First is the absence of rapidly available genotype information in the clinical workflow. This barrier is being overcome with whole-genome sequencing, which (with proper analysis) promises a permanent and largely immutable genetic roadmap for individual disease risk and drug response at a cost comparable to many other clinical tests.11 Second, we must have the knowledge to properly apply information on genetic variants for the diseases we are managing and the drugs we are using. As we describe, this knowledge is accumulating for heart failure and for other cardiac conditions, and the rate at which we are gaining additional information and developing further expertise appears to be accelerating.

The third and perhaps most formidable barrier is the lack of clinical evidence showing how real-time application of genetic information can best benefit patients. As has been broadly communicated to the medical community and lay public, common functional gene variants in CYP2C19 can impair the transformation of clopidogrel into its active metabolite, leading to increased risk of stent thrombosis after percutaneous coronary intervention.12 The relevant question thus becomes the following: If physicians have this information at the time of clinical care and reacted by adjusting clopidogrel dose or substituting prasugrel, which is unaffected by CYP2C19genotype,13 would there be any improvement in clinical outcome? It is also important to consider whether any observed benefits justify the additional costs of genetic testing and for the alternate drug. Studies are currently examining these questions, and similar clinical trials will prospectively examine whether a genotype-guided strategy of warfarin dosing will be superior to the standard genotype-blinded approach in reaching target anticoagulation goals. At this time, there are no similar prospective, randomized, blinded trials of genotype-guided care for common heart failure.

Emerging Variants

The variants described here are established, but new ones are emerging. Although findings in heart failure genome-wide association studies have been limited, we can expect additional common heart failure variants to emerge as sample sizes increase.65 The CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium published a genome-wide association study of incident heart failure that tested for associations between >2.4 million HapMap-imputed polymorphisms in >20 000 subjects.7 They identified 2 loci associated with heart failure, rs10519210 (15q22, containing USP3 encoding a ubiquitin-specific protease) in subjects of European ancestry and rs11172782 (12q14, containing LRIG3encoding a leucine-rich, immunoglobulin-like domain-containing protein of uncertain function) in subjects of African ancestry.66 In a companion study using the same population and genotyping results, mortality analysis of the subgroup of individuals who developed heart failure implicated an intronic SNP in CMTM7 (CKLF-like MARVEL transmembrane domain-containing 7).67 These genetic associations require independent replication and further study to identify the underlying biological mechanisms.

A recently published genome-wide association study by a European consortium on dilated cardiomyopathy identified common variants in BAG3 (BCL2-associated athanogene 3) associated with heart failure57 and identified rare BAG3 missense and truncation mutations that segregate with familial cardiomyopathy. These findings were consistent with an earlier exome-sequencing study that identifiedBAG3 as a familial dilated cardiomyopathy gene and showed recapitulation of cardiomyopathy with BAG3 morpholino knockdown in zebra fish.68 Together, these studies convincingly support variation in BAG3 as a genetic risk factor of cardiomyopathy and heart failure. It is noteworthy that both common and rare functional variations were identified at this locus. A unifying hypothesis for these findings, which needs to be formally tested, is that common variants in BAG3 serve as proxies for rare functional BAG3 mutations with large effects. In this situation, the underlying genetic lesion is a rare variant with a large functional effect. This has recently been described for common variants in MYH6 that correlated with rare functional MYH6 variants to cause sick sinus syndrome.69 It is premature to speculate on the clinical applications of these newer findings.

Moving Knowledge to Practice

A small number of genomic variants have been identified that modify heart failure by affecting well-understood physiological systems. The principal barrier preventing their adoption in practice may be lack of evidence showing how application of this information can best be used for clinical benefit. Trials testing genotype targeting of antiplatelet therapy and anticoagulation will be completed in the coming years. The findings from these studies will likely determine the level of enthusiasm for conducting genotype-guided trials of β-blockers and RAAS antagonists in heart failure. Given that the lifetime risk of heart failure in the United States is estimated at 1 in 5, even a small favorable effect on heart failure prevention or outcome through use of genome-guided therapy has the potential for a large public health impact. We therefore believe that a near-term goal should be to conduct pharmacogenomic trials in heart failure based on our current understanding of heart failure variants.

Looking ahead, unbiased approaches will continue to reveal a large number heart failure-modifying variants (both common and rare). Based on experience in other complex phenotypes, such has height70 and plasma lipid levels,71 the underlying genetic mechanisms for many new heart failure variants will be completely unknown, and their sheer number will preclude detailed experimentation using murine models to figure them out. Leveraging these variants for clinical application is a challenge that we will be forced to confront.

As our ability to identify rare, disease-causing variants improves through personal genome sequencing, we will be faced with the additional problem of how best to estimate the disease risk conferred by a sequence variant for which there has been no biological validation. In probabilistic terms, because there are 3 billion nucleotides in the human genome and over twice that many humans on the planet, it is likely that a nucleotide substitution for every position is represented in someone. Obviously, it will be impossible to recombinantly express and functionally characterize every DNA variant that is going to be implicated in heart failure. Bioinformatics filters have been used to try and separate functionally significant from insignificant variants based on the likelihood of changing transcript expression or protein function. These tools are limited but will improve if we tailor their results to the known characteristics of each gene product. For example, current approaches to categorize amino acid substitutions as conservative or nonconservative based only on charge or side chains can be improved by molecular modeling that incorporates protein-specific structure-function information. This approach has been used to estimate the pathogenicity of myosin heavy chain (MHC) mutations in an effort to determine which mutations are likely to cause familial cardiomyopathy when linkage analysis is not feasible.72 In concept, this approach can be applied to any protein for which structure-function activities have been finely mapped to distinct domains.

A promising extension of this approach may be to use evolutionary genetics to infer disease causality. Again, using the MHC genes as examples, human genome data show a greater prevalence of nonsynonymous gene variants in MYH6, which encodes the minor cardiac α-MHC isoform, compared with the adjacent MYH7, which encodes the major β-MHC isoform. This disparity suggests a greater tolerance for protein changes in the α-MHC isoform and negative selection against these in β-MHC. We can infer, therefore, that amino acid changes are more likely to have adverse impacts in MYH7-encoded β-MHC. If this paradigm survives prospective testing, then the forthcoming explosion of individual genetic data not only will present a massive problem in interpretation, but also will provide the genetic information by which analyses of rare sequence variants across large unaffected populations can help to differentiate the tolerable variants from those that are more likely to alter disease risk.

Each Reference above is found in:

http://circgenetics.ahajournals.org/content/4/6/701.full

SOURCE: 

Circulation: Cardiovascular Genetics.2011; 4: 701-709

doi: 10.1161/ CIRCGENETICS.110.959379

 

Read Full Post »


Reprogramming Cell Fate

 

Reporter: Larry H.Bernstein, MD, FCAP

Kathy Liszewski: reporting Gordon Conference “Reprogramming Cell Fate” meeting
M. Azim Surani, Ph.D., Univ Cambridge
Source unknown: June 21, 2012;32(11)
They report two critical steps both of which are needed for exploring epigenetic reprogramming.  While females have two X chromosomes ,
  • the inactivation of one is necessary for cell differentiation.
  • Only after epigenetic reprogramming of the X chromosome can pluripotency be acquired.

Pluripotent stem cells can generate – any fetal or adult cell type but

    • don’t develop into a complete organism.
Pioneer transcription factors take the lead in – facilitating cellular reprogramming – and responses to environmental cues.
Multicellular organisms consist of
  • functionally distinct cellular types
  • produced by differential activation of gene expression.
They seek out and bind specific regulatory sequences in DNA, even though DNA is coated with and condensed into a thick fiber of chromatin.
The pioneer factor, discovered by Prof. KS Zaret at UPenn SOM in 1996, endows the competence for gene activity,
  • being among the first transcription factors to
  • engage and pry open the target sites in chromatin.
FoxA factors, expressed in the foregut endoderm of the mouse,are necessary for
  • induction of the liver program.
    •  nearly one-third of the DNA sites bound by FoxA in the adult liver occur near silent genes.
organ regeneration example from induced plurip...

organ regeneration example from induced pluripotent stem cells(iPS cell) (Photo credit: Wikipedia)

English: Pathway of stem cell differentiation

English: Pathway of stem cell differentiation (Photo credit: Wikipedia)

Read Full Post »


Engineered Pancreatic Tissues Could Lead to Better Transplants for Diabetics

Reporter: Aviva Lev-Ari, PhD, RN

Wednesday, August 15, 2012
By: Kevin Hattori

Technion researchers have built pancreatic tissue with insulin-secreting cells, surrounded by a three-dimensional network of blood vessels. The engineered tissue could pave the way for improved tissue transplants to treat diabetes.

The tissue created by Professor Shulamit Levenberg of the Technion-Israel Institute of Technology and her colleagues has some significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

Prof Levenberg
Prof. Shulamit Levenberg

 

The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones, Levenberg and colleagues said. When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice.

Transplantation of islets, the pancreatic tissue that contains hormone-producing cells, is one therapy considered for people with type 1 diabetes, who produce little or no insulin because their islets are destroyed by their own immune systems. But as with many tissue and organ transplants, donors are scarce, and there is a strong possibility that the transplantation will fail.

The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-to-cell communication, by secreting growth hormones and other molecules, that significantly improve the odds that transplanted tissue will survive and function normally.

The findings confirm that the blood vessel network “provides key survival signals to pancreatic, hormone-producing cells even in the absence of blood flow,” Levenberg and colleagues concluded in their study published in the journal PLoS One.

One reason transplants fail, Levenberg said, “is that the islets are usually transplanted without any accompanying blood vessels.” Until the islets begin to connect with a person’s own vascular system, they are vulnerable to starvation.

The 3-D system developed by the Technion researchers tackled this challenge by bringing together several different cell types to form a new transplantable tissue. Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure.

“The advantages provided by this type of environment are really profound,” said Xunrong Luo, an islet transplantation specialist at the Northwestern University Feinberg School of Medicine. She noted that the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant.

Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves, Levenberg and colleagues found.

The technology “is still far from tests in humans,” Levenberg said, but she noted that she and her colleagues are beginning to test the 3-D tissue scaffolds using human instead of mouse islets.

According to Northwestern’s Luo, the 3-D model demonstrated in the study “will have important and rapid clinical implications” if the same results can be replicated with human cells. “This model system also provides a good platform to study the details and mechanisms that underlie successful transplantation.”

The Technion-Israel Institute of Technology is a major source of the innovation and brainpower that drives the Israeli economy, and a key to Israel’s renown as the world’s “Start-Up Nation.” Its three Nobel Prize winners exemplify academic excellence. Technion people, ideas and inventions make immeasurable contributions to the world including life-saving medicine, sustainable energy, computer science, water conservation and nanotechnology.

American Technion Society (ATS) donors provide critical support for the Technion—more than $1.7 billion since its inception in 1940. Based in New York City, the ATS and its network of chapters across the U.S. provide funds for scholarships, fellowships, faculty recruitment and chairs, research, buildings, laboratories, classrooms and dormitories, and more.

 

http://www.ats.org/site/News2?page=NewsArticle&id=7567&news_iv_ctrl=1161

Read Full Post »


Reported by: Dr. Venkat S.Karra, Ph.D.

Last August, UPenn scientists announced the dramatic results of a tiny clinical trial of their immunotherapy approach, describing long-lasting remissions in leukaemia patients for whom standard therapies had stopped working. Trials are also underway for other leukaemias and for lymphoma, mesothelioma, myeloma and neuroblastoma, according to the university.

The therapy developed by UPenn’s Carl June is complicated. Vaccines prompt a patient’s immune system to attack dangerous cells through an approach, called chimeric-antigen-receptor immunotherapy – a genetically redesigned immune cells for a more powerful attack. In this therapy first, blood is collected from leukaemia patients and exposed to substances that activate T cells, powerful cells that launch and coordinate immune attacks. Next, the T cells are genetically modified to recognize and attack leukaemia cells. Finally, the altered cells are returned to the patient, where they are expected to proliferate until the cancer cells are gone.

Drug giant Novartis is making a multimillion dollar bet that a patient’s immune system can be cancer’s worst enemy. It is teaming up with scientists at the University of Pennsylvania (UPenn) in Philadelphia to develop and manufacture cancer immunotherapies.

In the US$20-million collaboration, announced today, Novartis, which is based in Basel, Switzerland, will get exclusive worldwide rights to these technologies.

source

http://blogs.nature.com/news/2012/08/novartis-gives-upenn-20-million-for-cancer-vaccine.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+news%2Frss%2Fnewsblog+%28News+Blog+-+Blog+Posts%29&WT.ec_id=NEWS-20120807

 

 

 

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults

Bradford C. Dickerson, MD and David A. Wolk, MD On behalf of the Alzheimer’s Disease Neuroimaging Initiative

Author Affiliations

From the Frontotemporal Dementia Unit, Department of Neurology, Massachusetts Alzheimer’s Disease Research Center, and Athinoula A. Martinos Center for Biomedical Imaging (B.C.D.), Massachusetts General Hospital and Harvard Medical School, Boston; and Department of Neurology, Alzheimer’s Disease Core Center, and Penn Memory Center (D.A.W.), University of Pennsylvania, Philadelphia.

Correspondence & reprint requests to Dr. Dickerson: bradd@nmr.mgh.harvard.edu

ABSTRACT

Objective: New preclinical Alzheimer disease (AD) diagnostic criteria have been developed using biomarkers in cognitively normal (CN) adults. We implemented these criteria using an MRI biomarker previously associated with AD dementia, testing the hypothesis that individuals at high risk for preclinical AD would be at elevated risk for cognitive decline.

Methods: The Alzheimer’s Disease Neuroimaging Initiative database was interrogated for CN individuals. MRI data were processed using a published set of a priori regions of interest to derive a single measure known as the AD signature (ADsig). Each individual was classified as ADsig-low (≥1 SD below the mean: high risk for preclinical AD), ADsig-average (within 1 SD of mean), or ADsig-high (≥1 SD above mean). A 3-year cognitive decline outcome was defined a priori using change in Clinical Dementia Rating sum of boxes and selected neuropsychological measures.

Results: Individuals at high risk for preclinical AD were more likely to experience cognitive decline, which developed in 21% compared with 7% of ADsig-average and 0% of ADsig-high groups (p = 0.03). Logistic regression demonstrated that every 1 SD of cortical thinning was associated with a nearly tripled risk of cognitive decline (p = 0.02). Of those for whom baseline CSF data were available, 60% of the high risk for preclinical AD group had CSF characteristics consistent with AD while 36% of the ADsig-average and 19% of the ADsig-high groups had such CSF characteristics (p = 0.1).

Conclusions: This approach to the detection of individuals at high risk for preclinical AD—identified in single CN individuals using this quantitative ADsig MRI biomarker—may provide investigators with a population enriched for AD pathobiology and with a relatively high likelihood of imminent cognitive decline consistent with prodromal AD.

 

Copyright © 2011 by AAN Enterprises, Inc.

http://www.neurology.org/content/early/2011/12/21/WNL.0b013e31823efc6c.abstract

 

 

Read Full Post »