Global Health Impacts of Vector-Borne Diseases: Workshop Summary | The National Academies Press
Reporter: Aviva Lev-Ari, PhD, RN
Reporter: Aviva Lev-Ari, PhD, RN
Posted in Virology - Vector-borne DIsease | Tagged Virology - Vector-borne DIsease | Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN

WordCloud Image Produced by Adam Tubman
Each year the recipient(s) of the Warren Alpert Foundation Prize are recognized at a scientific symposium hosted by Harvard Medical School.
OCTOBER 6, 2016 –
The CRISPR/Cas9 Revolution and Gene Editing
In honor of Rodolphe Barrangou, Emmanuelle Charpentier, Jennifer Doudna, Philippe Horvath, Viginijus Siksnys for remarkable contributions to the understanding of the CRISPR bacterial defense system and the revolutionary discovery that it can be adapted for genome editing.
Harvard Medical School
The Joseph B.Martin Conference Center
77 Avenue Louis Pasteur
Boston, MA 02115
RSVP: HMS_events@hms.harvard.edu
Seating available on a first-come first served basis
Opening Remarks
Barbara J McNeil, MD, PhD, Acting Dean, HMS
Warren Alpert a very prestiguos Prize for advancements in Medicine, Treatment of disease and alleviation of suffering
Clifford Tabin, MD, Prof. of Genetics at HMS
Featured Speakers include:
Rodolphe Barrangou, PhD
Todd R. Klaenhammer Distinguished Scholar in Probiotics Research
North Carolina State University
CRISPR-mediated immunity in bacteria: discovery and applications
and
Philippe Horvath, PhD
Senior Scientist
Dupont
CRISPR-mediated immunity in bacteria: discovery and applications
History
Applications for CRISPR
Perspective on last Decade
Emmanuelle Charpentier, PhD
Prof. Dr.; Scientific Member of the Max Planck Society, Max Planck Director
Professor, Umeå University
The transformative genome engineering CRISPR-Cas9 technology: lessons learned from bacteria
Jennifer Doudna, PhD
Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences/HHMI Investigator
University of California, Berkeley
The Future of Genome Engineering: Biology, Technology and Ethics
BIOLOGY
TECHNOLOGY
INTERFERENCE
ETHICS
Virginijus Siksnys, PhD
Professor and Chief Scientist/Department Head, Institute of Biotechnology
Vilnius University
From mechanisms of microbial immunity to novel genome editing tools
Invited Speakers:
Luhan Yang, PhD
Chief Scientific Officer
eGenesis
Rewriting the pig genome to transform Xenotransplantation
Obstacles for Xenotransplantation
viral transmission
immunological Incompatibility
FUTURE
Austin Burt, PhD
Professor of Evolutionary Genetics
Imperial College London
Developing CRISPR-based gene drive for malaria control
For remarkable contributions to the understanding of the CRISPR bacterial defense system and the revolutionary discovery that it can be adapted for genome editing.
For their pioneering discoveries in chemistry and parasitology, and personal commitments to translate these into effective chemotherapeutic and vaccine-based approaches to control malaria – their collective work will impact millions of lives globally particularly in the developing countries.
For seminal contributions to our understanding of neurotransmission and neurodegeneration.
For their seminal contributions to concepts and methods of creating a genetic map in the human, and of positional cloning, leading to the identification of thousands of human disease genes and ushering in the era of human genetics.
For the discovery, preclinical and clinical development of bortezomib to FDA approval and front line therapy for the treatment of patients with multiple myeloma.
In recognition of their extraordinary contributions to medicine and innovations in bioengineering.
For the expansion and differentiation of human keratinocyte stem cells for permanent skin restoration in victims of extensive burns.
For the discovery, characterization and implementation of laser panretinal photo-coagulation, which is used to treat proliferative diabetic retinopathy.
For work leading to the development of a vaccine against human papillomavirus.
For their contribution to the development of the breast cancer therapy Herceptin, the first target-directed cancer treatment for solid tumors.
For discovering angiogenesis and its relationship to disease, and for championing the concept of anti-angiogenic therapies.
For her seminal contributions to the understanding of how the antitumor agent Taxol kills cancer cells.
For their pioneering work on the purification, characterization, and cloning of human interferon-alpha.
For his pioneering work in understanding the role of vitamin A supplementation in preventing blindness and life-threatening infections in children in the developing world.
For their pioneering work in cardiovascular research which has dramatically reduced the mortality rate for heart attacks.
For their research that contributed to the development of a drug that effectively treats chronic megelogenous leukemia and other forms of cancer.
For their research in the development of statins which lower the level of cholesterol in the heart.
For elucidating the pathway forming the leukotrienes and their role in bronchial asthma.
For their discoveries of molecules that regulate the growth and differentiation of bone marrow cells in health and disease.
For the development of the lung surfactant used for treating pulmonary hyaline membrane disease.
For identifying Helicobacter pylori as the organism that causes gastric and duodenal ulcers.
For discovering the enzymatic basis of Gaucher’s disease leading to its effective treatment.
For designing a powerful new approach to the treatment of high blood pressure and congestive heart failure.
For elaborating the genetics of Hepatitis B as the basis for its vaccine.
SOURCE
http://warrenalpert.org/prize-recipients
Posted in Intellectual Property, Interviews with Scientific Leaders, Nobel Prize Winners, Warren Alpert Foundation Prize Recipients | Tagged Warren Alpert Foundation Prize Recipients | Leave a Comment »
Reporter: David Orchard-Webb, PhD
Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT took place August 29-September 2, 2016 at the Marriott Long Wharf Boston, MA. The following is a synthesis of the Oncolytic Virus Immunotherapy stream.
Biomarkers
Biomarkers for patient selection in clinical trials is an important consideration for developing cancer therapeutics and immunotherapeutics such as oncolytic viruses in particular. Howard L. Kaufman, M.D., discussed the development of biomarkers for oncolytic virus efficaciousness and patient selection focusing on Imlygic (HSV-1). An important consideration for any viral therapy is the presence or absence of the receptors that the virus uses to gain entry to the cell. For example HSV-1 utilises Nectin and HVEM cell surface receptors and their expression levels on a patient’s tumour will influence whether Imlygic can gain entry and replicate in tumours. In addition he reported that B-RAF mutation facilitates Imlygic infection and that MEK inhibitors sensitise melanoma cell lines to Imlygic. Stephen Russell also presented data on the mathematical modelling of Vesicular Stomatitis Virus (VSV) tumour spread and the development of a companion diagnostic based on gene expression profiling to predict patients whose tumours will be readily infected.
The immune reaction triggered by oncolytic viruses is important to monitor. Howard L. Kaufman discussed immunogenic cell death and stated that oncolytic viruses trigger immunity through the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). He reported that immunosuppressive Tregs, PDL1 and IDO expression were associated with anti-cancer CD8+ T cell infiltration. Imlygic also promoted the tumour infiltration of monocytes which depending on the context may either be immunosuppressive or beneficial through recruiting natural killer (NK) cells. This highlights the importance of combining Imlygic with other immune modulating therapeutics that can modulate the immunosuppressive cells and messengers that are present in the tumour environment. He discussed the finding that high mutation burden is a marker for response to immune checkpoint inhibition (such as CTLA and PD1) and suggested that due to the fact that oncolytic viruses release tumour associated antigens (TAA) during cell lysis this may also be a predictive marker for oncolytic viral therapy immune response. Supporting this notion Stephen Russell reported that a patient that underwent complete remission of multiple myeloma plasmacytomas in response to a measles virus oncotherapy had a very high mutational burden.
Targeting the tumour stroma with adenoviral vectors
“VCN Biosciences SL is a privately-owned company focused in the development of new therapeutic approaches for tumors that lack effective treatment”. Manel Cascalló presented data from an ongoing phase I, multi-center, open-label dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without intravenous gemcitabine and Abraxane® in advanced solid tumors. Patients were selected based on low anti-Ad levels. Manel highlighted the problems of the pancreatic cancer matrix which limit intratumoral virus spread and also reduces chemotherapy uptake and tumour lymphocyte infiltration. VCN-01 expresses hyaluronidase to degrade the extracellular matrix and is administered intravenously. Liver tropism is reduced by replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK. VCN-01 replicates only in Rb tumour suppressor pathway dysregulated cancers, achieved through genetic modification of the E1A protein. In previous mouse xenograft studies of pancreatic and melanoma tumours VCN-01 showed efficaciousness in intratumoral spread, degradation of hyaluronan, and evidence of sensitisation to chemotherapy. The mouse models suggested that strategies that further target other major components of the ECM such as collagen and stromal cells may increase VCN-01 efficaciousness further [1]. The phase I trial supported safety and demonstrated that when administered intravenously VCN-01 reached the pancreatic tumour and replicated. In combination with gemcitabine and Abraxane® neutropenia was observed earlier than with chemotherapy alone. This is suggestive of increased efficaciousness of the chemotherapeutics as would be expected if a greater effective concentration reached the tumour. Biopsies suggested that VCN-01 shifted the balance of immune cells towards CD8+ T cells and away from immunosuppressive Treg.
Adenovirus tumor-specific immunogene (T-SIGn) Therapy
“PsiOxus Therapeutics Ltd develops novel therapeutics for serious diseases with a particular focus upon cancer”. Brian Champion discussed the application EnAd a chimeric Ad11p/Ad3 adenovirus which retains the Ad11 receptor usage (CD46 and DSG2). PsiOxus are developing Membrane-integrated T-cell Engagers (MiTe) proteins delivered via EnAd. These MiTe proteins are expressed at the cancer cell surface and engage with and activate T-cells. Their lead candidate NG-348 showed promising T-cell activation in vitro.
Vaccinia virus – overcoming the immunosuppressive cancer microenvironment
David Kirn provided a recent history of the oncolytic virus field and provided an overview of the validation of vaccinia virus over the period 2007-14 stating that it can produce cancer oncolysis, induce an immune response, and result in angiogenic ablation.
“Western Oncolytics develops novel therapies for cancer”. Steve Thorne discussed strategies to mitigate the immunosupressive environment encountered by oncolytic viruses. He presented data from models of tumours resistant to vaccinia oncolytic virus that Treg, and myeloid-derived suppressor cell (MDSC) numbers were higher whereas CD8+ T-cell levels were lower than in a sensitive model. He elaborated on a strategy of targeting the PGE2 pathway in order to reduce MDSC numbers entering the tumour microenvironment. He demonstrated that vaccinia virus expressing HPGD has reduced levels of MDSC in target tumours.
“Transgene (Euronext: TNG), part of Institut Mérieux, is a publicly traded French biopharmaceutical company focused on discovering and developing targeted immunotherapies for the treatment of cancer and infectious diseases”. Eric Quéméneur presented preclinical data on Transgene’s oncolytic vaccinia virus TG6002 which expresses a chimeric bifunctional enzyme which converts the nontoxic prodrug 5‐FC into the toxic metabolites 5‐FU and 5‐FUMP. This allows systemic delivery of the non-toxic prodrug chemotherapy with activation at tumours infected with the Vaccinia oncolytic virus. The virus plus prodrug combination was effective against all of the solid tumour cell lines tested. In addition the combination was effective against glioblastoma cancer stem-like cells. In pancreatic and colorectal cancer cell line models the vaccinia prodrug combination was synergistic or additive when combined with additional chemotherapeutics. In immunocompetent mouse models TG6002 increased the Tumour Teff/Treg ratio indicative of a shift from an immunosuppressive to an immunocompetent microenvironment. Furthermore in mouse models TG6002 induced an abscopal response.
Vesicular Stomatitis Virus (VSV) – A single shot cure for cancer?
“Vyriad strives to develop potent, safe and cost-effective cancer therapies in areas of unmet need”. Stephen Russell presented his position that oncolytic viruses could be a single shot cure for cancer. He emphasised the point that in oncolytic viral therapy the initial dose will be the most effective due to the relatively low levels of neutralising antibodies present and therefore defining the optimal dose is critical. The trend is for increased initial dose. Two IND’s have been accepted by the FDA, one for measles virus and the other for VSV.
John Bell described using VSV to deliver Artificial microRNAs (amiRNAs) to tumours. It was demonstrate that a VSV delivering ARID1A amiRNA was synthetic lethal when combined with EZH2 (methyl transferase) inhibition. He postulated that oncolytic viruses can be used to create factories of therapeutic amiRNAs transmitted throughout the tumour by exosomes.
HSV-1 an update on immune checkpoint combinations
Amgen was the first company to launch an FDA approved (October 2015) oncolytic virus, trade name Imlygic, which was developed by the UK based company Biovex. Jennifer Gansert gave a background on Imlygic and presented new data on combination with the CTLA4 inhibitor Ipilimumab. In mouse models abscopal response in contralateral tumours was 100% when a single tumour was treated with Imlygic combined with systemic delivery of anti-CTLA4. A Phase 1b clinical trial to test the combination in unresectable melanoma patients was completed and published in 2016. Fifty percent of the patients had durable response for greater than 6 months and 20% of the patients had ongoing complete response after a year of follow-up. Overall 72% of patients has controlled disease (no progression). In addition Amgen is recruiting for a phase III trial of the anti-PD1 Pembrolizumab in combination with Imlygic for unresectable stage IIIB to IVM1c melanoma.
“Virttu is a privately held biotechnology company, which has pioneered the development of oncolytic viruses for treating cancer”. Joe Connor discussed Seprehvir an oncolyic virus based on HSV-1 like Imlygic which is in clinical trials for which 100 patients have been treated to date. The trial data indicate that Seprehvir induces CD8+ T cell infiltration and activity as well as a novel anti-tumour immune response against select antigens such as Mage A8/9. Preclinical investigations focus on combination with checkpoint inhibitor antibodies, CAR-T targeted to GD2, and synergies with targeted therapies on the mTOR/VEGFR signalling axes.
Reovirus – an update
“Oncolytics Biotech Inc. is a clinical-stage oncology company focused on the development of oncolytic viruses for use as cancer therapeutics in some of the most prevalent forms of the disease”. Brad Thompson provided an update on REOLYSIN®, Oncolytics Biotech’s proprietary T3D reovirus. Highlights included concluding the first checkpoint inhibitor and REOLYSIN® study in patients with pancreatic cancer and preparing for registration study in multiple myeloma.
Maraba virus – privileged antigen presentation in splenic B cell follicles
Turnstone Biologics is developing “a first-in-class oncolytic viral immunotherapy that combines a bioselected and engineered oncolytic virus to directly lyse tumors with a potent vaccine technology to drive tumor-antigen specific T-cell responses of unprecedented magnitude”. Caroline Breitbach described Maraba MG1 Oncolytic Virus which was isolated from Brazilian sand flies. Their lead candidate is an MG1 virus expressing the tumour antigen MAGE-A3. In mouse models a combination of adenovirus-MAGE-A3 and MG1-MAGE-A3 in a prime-boost regimen produced extremely robust CD8+ T cell responses. It is thought that a privileged antigen presentation in splenic B cell follicles maximizes the T cell responses. A phase I/II trial is enrolling patients to test the adenovirus-MAGE-A3 and MG1-MAGE-A3 prime-boost regimen in patients with MAGE‐A3 positive solid tumours for which there is no life prolonging standard therapy.
Oncolytic virus manufacturing
Anthony Davies of Dark Horse Consulting Inc. reviewed the manufacturing hurdles facing oncolytic viruses and pointed out that thus far adenovirus is the gold standard. He discussed isoelectric focusing for virus manufacturing, process flow and the procurement of key raw materials. He emphasized the importance of codifying analytical methods, and the statistical design of experiments (DOE) for optimal use of finite resources.
Mark Federspiel described the difficulties associated with measles virus manufacturing which include the large pleomorphic size (100-300nm) which cannot be filter sterilized efficiently due to shear stress. As a result aseptic conditions must be maintained throughout the manufacturing process. There are also issues with genomic contamination from infected cells. He described improved manufacturing bioprocesses to overcome these limitations using the HeLa S3 cell line. Using this cell line resulted in less residual genomic DNA than the standard however it was still relatively high compared to vaccine production. There is still much room for improvement.
REFERENCES
Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, Moreno R, Bazan-Peregrino M, Cascalló M, Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015 Mar 15;21(6):1406-18. Doi: 10.1158/1078-0432.CCR-14-2213. Epub 2014 Nov 12. PubMed PMID: 25391696.
Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Immunotherapy, Oncolytic virus & OncoViro-Therapy | Tagged Cancer immunotherapy, Immunotherapy, Meeting Report, Oncolytic Viruses | Leave a Comment »
Curator: Aviva Lev-Ari, PhD, RN
@pharma_BI @Pharma_BI 18m18 minutes ago
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Curator & Reporter: Aviva Lev-Ari, PhD, RN
Curator: Aviva Lev-Ari, PhD, RN
Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?
Curator & Reporter: Stephen J. Williams, Ph.D.
Reporter: Aviva Lev-Ari, PhD, RN
Licensing Agreements for CRISPR/Cas9 Genome Editing Technology Patent
Curator: Aviva Lev-Ari, PhD, RN
Genentech dives into mRNA, betting $310M on BioNTech’s personalized cancer vaccine tech
Messenger RNA (mRNA) Therapeutics™ hold the potential to transform medicine across multiple drug modalities and therapeutic areas. As the first mover and leading company in the space, our responsibility is to simultaneously advance promising internal development programs, while also mobilizing an entire ecosystem capable of propelling the field forward for patients.

We form wholly-owned ventures to focus dedicated resources and staff in key disease areas where high unmet medical needs demand safe, efficacious and innovative therapies.
We are incubating additional ventures in diverse therapeutic areas, leveraging a cross-section of relevant modalities.
Moderna is working with world leaders in key therapeutic areas where our mRNA Therapeutics™ can potentially have a profound impact on patients’ lives. We enjoy close and productive strategic agreements with:
SOURCE
http://www.modernatx.com/our-business-model
Building from our mRNA core expression platform, we have created a new scale of drug discovery and development that enables a series of new drug modalities. Each modality represents a distinct approach to using the mRNA platform to encode proteins that achieve a therapeutic benefit, enabling us to develop numerous drug candidates across a wide array of therapeutic areas.

Vaccines are substances that teach the immune system to rapidly recognize and destroy invading pathogens such as bacteria or viruses, preparing the body’s adaptive immunity for future exposure to the pathogen. Historically, vaccines have introduced immune-activating markers from pathogens into the body. Conversely, Moderna is developing mRNA-based vaccines that enable the body to produce and present immunogenic proteins to the immune system.
Moderna is also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Moderna’s technology allows for a rapid turn-around time in production of these unique mRNA vaccines.

Many diseases are caused by defects in proteins that function inside cells. Existing methods of protein-based therapy do not allow for proteins to reach the intracellular space, and as such are unable to replace the defective, disease-causing proteins within cells. Moderna’s platform allows for the development of mRNA therapies that can stimulate production of intracellular proteins as well as transmembrane proteins. This could potentially lead to a novel approach to treating a vast array of rare genetic and other diseases caused by intracellular protein defects.

Many targets for the treatment of cancer have been identified but their therapeutic potential has been limited by either the inability to access these targets, or by systemic toxicities. Moderna’s platform allows for localized expression of therapeutic proteins within the tumor microenvironment.

Antibodies are secreted proteins that bind to and inhibit specific targets. Moderna’s platform has the potential to stimulate the body’s own cells to produce specific antibodies that can bind to cellular targets.

Proteins are large, complex molecules that have many critical functions both inside and outside of cells. Moderna’s platform stimulates cells to produce and secrete proteins that can have a therapeutic benefit through systemic exposure.
SOURCE
At Moderna, we are pioneering the development of a new class of drugs made of messenger RNA (mRNA). This novel drug platform builds on the discovery that modified mRNA can direct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructs that can have therapeutic activity inside and outside of cells.
Our efforts are helping Moderna and the industry to flatten the mRNA learning curve across the full breadth of competencies needed to drive the platform forward, including chemistry, mRNA biology, formulation, process development, automation and high-throughput production, quality, and Good Manufacturing Practice (GMP) manufacturing.

SOURCE
Posted in mRNA Therapeutics | Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
“Maybe there is a way to use one drug to alter the mitochondrial signal and another drug to alter the communciation signal from the brain,” he said. “You would never see these two effects if you were studying protein folding in a tissue culture dish, because you don’t have the whole organism, C. elegans, in which you can look at the signals being communicated.”
Co-authors of the fat study include Hyun-Eui Kim, Ana Rodrigues Grant, Milos Simic, Rebecca Kohnz, Daniel Nomura, Jenni Durieux, Celine Riera, Melissa Sanchez, Erik Kapernick and Suzanne Wolff at UC Berkeley. The second study was co-authored by Kristen Berendzen, Jenni Durieux, Ye Tian, Hyun-eui Kim and Suzanne Wolff of UC Berkeley, in collaboration with Li-Wa Shao and Ying Liu of Peking University in Beijing.
The studies are supported by the Howard Hughes Medical Institute, National Institutes of Health, Glenn Foundation for Medical Research, and Jane Coffin Childs Memorial Fund for Medical Research.
RELATED INFORMATION
SOURCE
http://news.berkeley.edu/2016/09/08/can-some-types-of-fat-protect-us-from-brain-disease/
Posted in Innovations in Neurophysiology & Neuropsychology | Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
“In bringing together three world-class research organizations in UC Berkeley, UCSF and Stanford, the Biohub represents the kind of cross-institutional collaborative environment that will be necessary for addressing the most pressing life sciences challenges of our time,” said UC Berkeley Chancellor Nicholas Dirks. “Each of these institutions brings its own set of perspectives, questions, ideas and expertise to this venture, and, given this unprecedented kind of exchange, I have no doubt that the Biohub will be the catalyst for major research breakthroughs.”
“This exciting new venture by the Chan Zuckerberg Initiative brings together private philanthropy with some of the best minds in the world,” said Janet Napolitano, president of the University of California. “Collaboration in the name of science and the public good among the Bay Area’s three leading research universities will surely speed the development of new treatments and cures for diseases once deemed intractable.”
Posted in BioTechnology - Venture Creation, Venture Capital | Leave a Comment »