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George Stamatoyannopoulos Lecture 200 8:00 AM - 9:15 AM Room: Ballroom AB George Stamatoyannopoulos Lecture
ChairXandra O. Breakefield, PhD
Speakers
Craig Mello, PhD Surveillance of Transcription and Persistent Silencing of Foreign Sequences in the C. Elegans Germline Organisms exhibit a fascinating array of gene-silencing pathways, which have evolved, in part, to confront invasive nucleic acids such as transposons and viruses. Not surprisingly, these pathways are highly active in the germline and can be elicited upon the introduction of transgenes. A key question raised by the existence of these pathways is how do they distinguish self- from non-self nucleic acids? Evidence exists for a number of cues that might facilitate the recognition of foreign sequences including, copy-number sensing, sensing of unpaired DNA, or the sensing of aberrant RNA (e.g. dsRNA). Here we report on a remarkable silencing pathway that can permanently silence even single-copy transgenes. We show that the initiation of silencing depends on the piwi Argonaute PRG-1 and its genomically encoded piRNA cofactors. Our findings support a model in which PRG-1 scans for foreign sequences while two other Argonaute pathways serve as epigenetic memories of "self" and "non-self" RNAs. These findings suggest that organisms utilize RNAi-related mechanisms to keep inventory of all genes expressed in the germ-line, and to recognize and silence foreign genes.
Exhibit Hall Coffee Social 9:15 AM - 10:00 AM Room: Hall A
Scientific Symposium 210 10:00 AM - 12:00 PM Room: 201 C Cellular Approaches to the Immunotherapy of Cancer In Memoriam of Ralph M. Steinman, MD
Co-ChairsAndrew Byrnes, PhD Shulin Li, PhD
Thomas A. Ferguson, PhD Harnessing the Power of Dendritic Cells, Apoptotic Cells, and DAMPs to Treat Infection Sepsis is a leading cause of mortality in intensive care units characterized as the host response to overwhelming infection or injury leading to immune dysfunction and organ damage. Septic patients become severely immunosuppressed making them susceptible to secondary infections due to defects in adaptive immunity resulting from effector cell apoptosis and the induction of immune tolerance by apoptotic cells. High-mobility group box-1 (HMGB1) is an important mediator in sepsis lethality; however, it role in adaptive immunity following sepsis is unknown. HMGB1 function in the adaptive immune responses is dependent on processing by caspase 1 via the Nlrp3 inflammasome. Caspase 1 cleavage of HMGB1 produces an immunogenic fragment within the A box and a redox sensitive peptide within the B box. The A box fragment, when fed to DC in the presence of apoptotic cells, can program DC to boost protective immunity and increase survival to Candida albicans following severe sepsis. In contrast, the B Box fragment when administered with DC and apoptotic cells severely suppressed immunity and increased susceptibility to secondary Candida infection. These results reveal an intricate link between apoptosis, the inflammasome and the regulation of the alarmin function of HMGB1 and have direct therapeutic implications in infectious diseases.
Daniel J. Powell, PhD Engineering T cells for Universal Treatment of Cancer Successful adoptive immunotherapy of cancer is reliant upon the ability to generate T lymphocytes with high avidity for cancer antigens, however, the identification, isolation and expansion of naturally-occurring tumor-reactive T cells in many cancers has challenged their clinical application. Gene engineering resolves this issue though the de novo generation of T cells with redirected specificity for cancer antigen via transfer of genes encoding for exogenous T cell receptors or chimeric immune receptors. Importantly, transfer of additional genes encoding for a variety of secondary receptors or effector molecules can further instill T cells with favorable attributes for clinical application including enhanced proliferation, survival and potency in vivo. A wave of innovative, new advances in cell selection, culture conditions and gene modification strategy now stands to improve the efficacy and safety of the engineered T cell platform, as well as increase patient accessibility to this promising and potent clinical approach for advanced malignancies.
David B. Weiner, PhD Synthetic Chemistry to Invivo Immunology the Evolution of Enhanced DNA Vaccine Technology DNA vaccines are an important novel technology, which has many conceptual advantages over traditional vaccine modalities. However, in humans the immune potency of this approach has been weak. We have developed a combination of technologies for plasmid optimization, adjuvant technology and enhanced EP delivery which collectively result in dramatically improved invivo gene delivery and immune potency in large primates and humans. These new DNA approaches can produce immune response similar or superior to live viral vectors. We will present data in animal models and in human studies that illuminate specific features of these improved DNA vaccine and benchmark their development against other important technologies. These studies have critical implications for the expansion of this platform targeting difficult pathogens and in cancer immune therapy settings.
Jose R. Conejo-Garcia, MD, PhD Therapeutic anti-tumor Immunity Induced by Synthetic microRNA-carrying Nanoparticles Targeting tumor-induced immunosuppression starts producing impressive clinical results as an individual intervention, and will be a requirement for the implementation of anti-tumor immunotherapies as first-line treatments in the future. We found that nanoparticle-mediated delivery of synthetic immunostimulatory microRNAs, specifically to tumor-associated leukocytes, is sufficient to re-program immunological control of metastatic ovarian cancers. RNA duplexes mimicking the bulged structure of endogenous pre-miRNAs were effectively processed into functional mature miRNAs, which elicited dramatic changes in nearly half of transcripts in these plastic leukocytes. Our results provide a platform for non-viral delivery of functional miRNA mimetics, which has obvious implications for therapeutic purposes, and also as a research tool to define mRNA targets.
Scientific Symposium 211 10:00 AM - 12:00 PM Room: Ballroom AB Clinical Trials I
ChairPhilip R. Johnson, MD
Bruce Sullenger, PhD Driving Innovation by Forward and Reverse Translation with Aptamers Thrombosis remains the major cause of death and disability in the western world. We will describe our recent efforts to develop RNA aptamers to control thrombosis by targeting coagulation factors and platelet proteins. We will present recent preclinical and clinical studies evaluating the ability of aptamers targeting individual or combinations of coagulation factors. We have observed that combinations of aptamers that target multiple steps in the coagulation cascade are extremely potent inhibitors of clotting. We will also present recent work demonstrating that aptamers targeting VWF are potent antithrombotic agents in mammalian models of stroke. However as expected from studies on VWF knock out mice and humans lacking VWF, such VWF aptamers also engender significant bleeding when animals are surgically challenged. To control such bleeding in the surgical setting, we also will describe the development of two different antidote molecules that counteract aptamer activity. Furthermore, we will discuss results indicating that one of these types of antidotes, nucleic acid scavengers, have intrinsic anti-thrombotic activity themselves as well as anti-inflammatory properties. Thus we believe that nucleic acid scavengers may represent novel therapeutic agents to combat thrombotic and inflammatory diseases caused by release of nucleic acids into the extracellular space.
Philip R. Johnson, MD Immunoprophylaxis by Gene Transfer: Shortcut to an HIV Vaccine The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. We have taken a markedly different approach to an HIV vaccine, wherein we use adeno-associated virus gene transfer vectors to express antibodies or antibody-like moleccules with predetermined anti-HIV specificity. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.
Raymond T. Bartus, PhD The Development of AAV2-neurturin (CERE-120) for Parkinson’s Disease: A Review of the Challenges and Translational Issues Confronted During the Course of Establishing 'Clinical Proof of Concept' CERE-120 (AAV2-NRTN), a gene delivery construct expressing only the human neurotrophic factor protein, neurturin (NRTN), is designed to rejuvenate degenerating nigrostriatal neurons in Parkinson’s disease (PD). It represents one of the more mature gene transfer programs, in that over two dozen nonclinical studies and 3 clinical trials have been completed, with dosing recently completed (and assessments continuing) for a fourth, pivotal clinical trial. In total, eighty Parkinson’s disease (PD) subjects have received CERE-120 (some over 7 years ago), with over 250 cumulative years exposure, and no serious safety issues identified. A prior double-blind controlled Phase 2a trial supported the safety and established clinical proof of concept via significant benefit on several protocol-prescribed, blinded motor and QOL endpoints at 12 and 18 mo. Although no measure favored the sham control, the trail failed to meet the primary endpoint (UPDRS motor-off at 12mo). Autopsy tissue from two CERE-120-subjects, who later died of unrelated causes, provided the first evidence that gene therapy can increase expression of a neurotrophic factor in PD brains and that clear but modest enhancement of degenerating neurons can be induced. However, this analysis also revealed that serious deficits in retrograde transport exist in these degenerating neurons, impeding the transport of NRTN from the targeted putamen to the SN, thus limiting exposure to repair genes located in the degenerating cell bodies. A new Phase 1/2b clinical protocol was developed which incorporated the insight gained from the initial controlled trial, including the need to target both the degenerating cell bodies in SN and terminal field (putamen). This presentation will discuss some of the more important translational issues confronted during the 10-year development of CERE-120, leading up to the current, pivotal trial intended to replicate and extend to safety and efficacy data base that exists for CERE-120, as a treatment for PD.
Sean Savitz, MD Bone Marrow Mononuclear Cells for the Treatment of Acute Ischemic Stroke The learning objectives are: To learn about different types of cell therapies as new treatment approaches to stroke. To learn how cell therapies are tested in animal models. To learn how cell therapies are tested in clinical trials.
Scientific Symposium 212 10:00 AM - 12:00 PM Room: 204 C Gene and Cell Therapy Impact on Disorders in Pulmonary Medicine: A Broader View
Co-ChairsTerence R. Flotte, MD Jay K. Kolls, MD
Jay K. Kolls, MD Mucosal Prime Boosting to Prevent Opportunistic Pulmonary Infections AIDs results in increased susceptibility to pulmonary opportunistic infections including bacterial pneumonia and fungal infections such as Pneumocystis infection. Using fungal proteomics to discover B-cell antigens and a prime boost vaccine approach with the molecular adjuvant CD40L we have been able to elicit mucosal immune responses in the setting of CD4 T-cell deficiency that has therapeutic efficacy in preventing AIDs related pulmonary infections. These data will be discussed as well the clinical development path for pre-clinical toxicology and human phase I clinical trials.
Steven M. Albelda, MD Combining Immuno-gene Therapy Using Ad.INFalpha with Chemotherapy to Treat Malignant Mesothelioma: From Bench to Bedside One promising approach to cancer therapy is in-situ tumor vaccination using gene therapy vectors that stimulate anti-tumor immunity. Our group has used this approach by directly delivering type 1 interferons encoded by a non-replicating adenovirus into malignant mesothelioma tumors using pleural catheters. Although we have shown significant anti-tumor immune and clinical responses in some patients, most vaccines require repeated administration to maintain anti-tumor immune responses. Since neutralizing antibodies prevent repeat adenoviral vector instillation, we have developed an alternative strategy that we call “reverse vaccination”. In this approach, we use Ad.IFN gene therapy to initiate an anti-tumor immune response and boost this response using repeated cycles of standard chemotherapy. Our animal studies have shown that the chemotherapy is able to markedly enhance efficacy of immune-gene therapy through multiple mechanisms including increases in antigen specific T cells in the spleen, decreases in inhibitory cell populations (Tregs, myeloid suppressor cells, and B cells) in the spleen, significant increases in total numbers of CD8 cells and activated T cells in the tumor, increased total numbers of antigen-specific (tetramer+) CD8 T cells in the tumor, and a reduction in inhibitory macrophages within the tumor. Based on these data, we began a clinical trial in which mesothelioma patients first receive intrapleural Ad.INFalpha plus celecoxib followed in two weeks by standard first or second line chemotherapy. Very significant anti-tumor responses (more than expected by chemotherapy alone) have been observed on CT scanning without significant toxicity. Our data suggest that combining immune-gene therapy with chemotherapy may significantly improve the treatment of mesothelioma. These concepts should be applicable to other cancers.
Christian Mueller, PhD Dual Function Vectors to Treat AAT Deficiency a-1 antitrypsin deficiency can exhibit two pathologic states: a lung disease that is primarily due to the loss of AAT's antiprotease function, and a liver disease resulting from a toxic gain-of-function of the mutant protein. We have developed several recombinant adeno-associated virus vectors that incorporate microRNA sequences targeting the AAT gene while also driving the expression of miRNA-resistant wild-type AAT gene, thus achieving concomitant Z-AAT knockdown in the liver and increased expression of M-AAT.
Joseph Zabner, MD Gene Therapy for Cystic Fibrosis Lung Disease. Lessons from a Pig Model Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). We recently generated pigs with mutated CFTR genes. Within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. We studied newborn pigs and found that lungs showed no inflammation but were less often sterile than controls and CF pigs failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Using directed evolution in pigs airway epithelia in vivo, we selected an AAV that efficiently transfers genes into airway epithelia nad may be able to correct the lung phenotype in CF pigs.
Scientific Symposium 213 10:00 AM - 12:00 PM Room: 201 AB Progress in Europe
Co-ChairsThierry C. VandenDriessche, PhD Christopher Baum, MD
Jose Sahel, MD Photoreceptor Degeneration: From Gene Correction in Stargardt Diseases to Vision Restoration by Optogenetics Currently, there is no known effective treatment that can prevent or reverse the vision loss in Stargardt's disease, the most common form of juvenile macular degeneration that is caused by mutations in the photoreceptor-specific ABCA4 gene. In animal models of this disease, improved retinal morphology and function have been observed after subretinal administration of viral vectors containing the human ABCA4 gene, providing evidence of the potential therapeutic efficacy of gene therapy. Indeed, the first-ever gene-based therapy clinical trial for treatment of Stargardt’s disease is currently underway. Recently, a genetic approach for delivering cell type–specific optical control, known as optogenetics, has been shown to restore the visual function of the remaining defective or “dormant” cone photoreceptors in retinal degenerative disease. Having the distinct advantage of being independent of the underlying genetic defect, optogenetics opens new horizons for treatment of Stargardt’s disease and other currently untreatable blinding diseases.
Salima Hacein-Bey Abina, PharmD, PhD Clinical Benefit after SIN-Retroviral Gene Therapy in SCID-X1
Anne Galy, PhD International Clinical Trials of Hematopoietic Gene Therapy for Wiskott Aldrich Syndrome Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency (PID). One of the first diseases to be successfully treated by allogeneic hematopoietic stem cell transplantation, WAS is currently the subject of several phase I/II gene therapy trials for patients without HLA-compatible donors. Encouraging preclinical efficacy and safety results using refined lentiviral vectors, and the development of robust clinical-grade manufacturing processes have supported the initiation of several phase I/II studies. Ongoing international efforts in London, Paris and Boston to coordinate trials of gene therapy for the WAS will be presented and may provide a model for the expedited development of new treatments for other rare diseases.
Scientific Symposium 214 10:00 AM - 12:00 PM Room: 202 AB Delivery in the 21st Century: NIH Resources
ChairSteven J. Zullo, PhD
Sonia I. Skarlatos, PhD Gene Therapy Resources - Viral Vectors GTRP, Fetal Center, National Gene Vector Biorepository
Steven J. Zullo, PhD Non-viral Gene Delivery
Sara Hook, PhD Non-viral Gene Delivery
Mahendra Rao, MD, PhD What is New at NIH for Stem Cell Research?
Jacqueline Corrigan-Curay, MD, JD Overview of National Center for Advancing Translational Sciences (NCATS)
Daniel Rosenblum, MD Overview of National Center for Advancing Translational Sciences (NCATS)
Philip J. Brooks, PhD Gene Therapy for Rare Diseases
Frederick P. Ognibene, MD NIH Clinical Center: New Opportunities for Collaboration
Scientific Symposium 215 10:00 AM - 12:00 PM Room: 204 AB Novel Targeting Methods for Cell and Gene Delivery
ChairMark H. Tuszynski, MD, PhD
James L. Funderburgh, PhD Stem Cell Therapy for Corneal Blindness The cornea, the transparent tissue at the anterior of the eye is the entry portal for light into the visual system. Corneal scarring from infections and trauma permamently disrupts vision for millions of individuals world-wide and currently is only treated by corneal transplantation. Although bioengineering of corneal prostheses is making progress, our research is investigating direct remediation of corneal scars using cell-based therapy. We have identified mesenchymal stem cells in adult corneas which can be expanded extensively without loss of the potential to differentiate into corneal keratocytes. In a mouse model of corneal haze direct injection of corneal stromal stem cells resulted in restoration of organized extracellular matrix, corneal thickness and transparency. Our current focus is expansion of autologous human stem cells in xeno-free cultures that may be used in clinical trials.
Steven J. Gray, PhD Engineered AAV Capsids Tailored for Specific Therapeutic Applications Recent advances in AAV capsid engineering techniques have vastly expanded the ability to develop novel AAV variants. The overall goal is to “personalize” vectors, taking advantage of a disease state or delivery paradigm, to specify gene targeting to areas of pathology or tailoring the vector biodistribution to target specific organs while minimizing delivery to potentially detrimental targets. Similar any typical drug optimization, these approaches aim to: 1) increase potency and 2) decrease off-target effects. For viral vector capsid design, this translates to increasing the tropism for the desired cell/tissue, reducing the tropism for undesired cells/tissues, avoiding potential immunological barriers, and/or improving cellular trafficking/uncoating, all in the context of a given route of administration and disease application. As the potential of naturally occurring AAV capsids is pushed to the limit, newer engineered capsids promise to be more potent and more specific, increasing both the safety and efficacy of gene transfer.
Mark H. Tuszynski, MD, PhD Growth Factor Gene Delivery for Alzheimer's Disease This presentation will address two gene delivery programs for Alzheimer's disease (AD). This first program, Nerve Growth Factor (NGF) Gene Delivery for Alzheimer's disease, is currently the subject of Phase 2 multi-center trials. The second program, Brain Derived Neurotrophic Factor (BDNF) Gene Delivery for Alzheimer's disease, is in the final phase of preclinical studies leading to the filing of an IND. Both programs aim to prevent the death of vulnerable neurons in the AD brain, and stimulate the function of remaining neurons. NGF targets basal forebrain cholinergic systems, a key neuromodulatory system that degenerates in AD. BDNF directly targets the loss of important memory circuitry of the brain in the entorhinal cortex and hippocampus.
Gustavo D. Aguirre, VMD, PhD Photoreceptor Targeting in Achromatopsia and RPGR-X-linked RP; Rescuing Function and Preserving Structure Inherited gene defects can affect photoreceptor function and viability; two examples of these model diseases in dogs, achromatopsia, a CNGB3 channelopathy, and RPGR-X-linked retinal degeneration, provide new insights into photoreceptor-specific gene augmentation with promising translational applications. Targeting CNGB3 mutant cones with a therapeutic rAAV2/5-hCNGB3 vector driven by the long version of the human red cone opsin promoter leads to recovery of cone function that has been stable for >4 years. Gene augmentation by subretinal injections of AAV2/5-vectored human RPGR with human IRBP or GRK1 promoters showed preserved photoreceptor nuclei and inner/outer segments only in treated areas, and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Efficacy of gene therapy in these large animal models of achromatopsia and X-linked RP provides a path for translation to human treatment.
Scientific Symposium 216 10:00 AM - 12:00 PM Room: 203 AB Translating Stem Cells into Therapy
ChairJane S. Lebkowski, PhD
Anthony Ting, PhD Clinical Development of Adherent Adult Stem Cells
Ira J. Fox, MD Overcoming Barriers to Successful Cell Therapy to Treat Liver Disease Patients with life-threatening liver-based metabolic disorders require organ transplantation even though their metabolic diseases are typically the result of a single enzyme deficiency, and the liver otherwise functions normally. Hepatocyte transplantation holds great promise as an alternative to organ transplantation for the treatment of liver disease, and numerous studies in rodents indicate that transplants consisting of isolated liver cells can correct metabolic deficiencies of the liver. Clinically, the transplant procedure is far less intrusive than replacement of the whole liver, and because the native liver is not removed, the transplanted hepatocytes need only improve the metabolic deficiency and need not replace all hepatic functions. Thus far, clinical trials of hepatocyte transplantation have demonstrated its long-term safety, but only partial correction of metabolic disorders has been achieved. Based on extensive small and large animal studies, we have shown that conditioning part of the liver with low-dose focused radiation facilitates repopulation of the native liver by transplanted hepatocytes, can result in complete correction in models of hereditary metabolic deficiencies of the liver, and has led to the initiation of an FDA-approved clinical trial for the treatment of children and young adults with metabolic liver diseases.
Lee L. Rubin, PhD A Stem Cell Approach to Understanding and Treating Spinal Muscular Atrophy (SMA) Most degenerative diseases of the nervous system are caused by neuron-selective cell death. SMA, the most common of the childhood neural disorders, is caused by mutations in the Survival of Motor Neuron (SMN) gene and is typified by motor neuron malfunction and death. Human and mouse stem cells with SMN mutations can be produced and used to generate large numbers of these defective motor neurons. The availability of these cells has permitted the types of studies and assays that were impossible just a few years ago. This has initiated a new era of experimentation focused on identifying treatments to prolong motor neuron survival.
Steven D. Schwartz, MD Human Embryonic Stem Cell Derived Retinal Epithelium for Treatment of Macular Degeneration Phase I Results
Lunch Break (On Own - Not Provided) 12:00 PM - 1:15 PM
Meet the Investigator Lunch Session 220 12:00 PM - 1:15 PM Room: Marriott 303 Career Development: Academic vs. Industry
Barrie J. Carter, PhD
Douglas J. Jolly, PhD
Meet the Investigator Lunch Session 221 12:00 PM - 1:15 PM Penn Vector Core Facility Tour (University of Pennsylvania)
Julie C. Johnston, PhD
Oral Abstract Session 230 1:15 PM - 3:15 PM Room: Ballroom AB Clinical Gene & Cell Therapy
Co-ChairsKatherine A. High, MD David H. Kirn, MD
Oral Abstract Session 231 1:15 PM - 3:15 PM Room: 201 C DNA Vector Development and Gene Targeting
Co-ChairsToni Cathomen, PhD Matthew H. Wilson, MD, PhD
Oral Abstract Session 232 1:15 PM - 3:15 PM Room: 201 AB Gene and Cell Therapy for Genetic and Metabolic Disorders: Monogenic and Metabolic Disorders
Co-ChairsVirginia A. Haurigot, PhD Roland W. Herzog, PhD
Oral Abstract Session 233 1:15 PM - 3:15 PM Room: 202 AB CNS: Neurodegenerative
Co-ChairsNicholas Boulis, MD Marco A. Passini, PhD
Oral Abstract Session 234 1:15 PM - 3:15 PM Room: 204 AB Cancer - Targeted Gene & Cell Therapy
Co-ChairsEvanthia Galanis, MD, DSc Neil Senzer, MD
Oral Abstract Session 235 1:15 PM - 2:15 PM Room: 204 C Physical Methods of Gene Delivery
Co-ChairsLluis M. Mir, PhD, DSc Kevin G. Rice, PhD
Oral Abstract Session 236 1:15 PM - 2:15 PM Room: 203 AB Cardiovascular Gene & Cell Therapy
Co-ChairsLucio Pastore, MD, PhD (Invited)Thomas Weber, PhD
Oral Abstract Session 237 2:25 PM - 3:25 PM Room: 204 C Engineering of Gene Regulation
Co-ChairsPhilip D. Gregory, DPhil Punam Malik, MD, PhD
Oral Abstract Session 238 2:25 PM - 3:25 PM Room: 203 AB Lung & Respiratory Disease
Co-ChairsRoberto Cattaneo, PhD Patrick L. Sinn, PhD
Exhibit Hall Open: Networking Reception & Poster Session I 3:30 PM - 5:30 PM Room: Hall A
Foundation Symposium 240 5:45 PM - 8:15 PM Room: 202 AB AFM/MDA Symposium and Reception
Jointly planned by the Association Francaise contre les Myopathies and the Muscular Dystrophy Association
Co-ChairsKathryn R. Wagner, MD, PhD
Christopher M. Walker, PhD
Katherine A. High, MD Anti-capsid Immunity I
James M. Wilson, MD, PhD Ant-capsid Immunity II
Michael R. Betts, PhD Anti-vector and Transgene Immunity
Oumeya Adjali, MD PhD Modes of Vector Delivery and Immune Issues in Preclinical Studies
William J. Powers, MD Route of Administration - Human Studies We conducted a dose escalation study of high-pressure transvenous perfusion with 0.9% saline in the lower and upper extremities of adult patients with muscular dystrophy to test the safety and feasibility of this methodology for single-limb trials of gene transfer. Results in 9 or more subjects will be presented including safety monitoring for nerve, muscle or vascular damage and efficacy assessment with magnetic resonance imaging of muscle water content.
Otto-Wilhelm Merten, PhD AAV Production Gene therapy of neuromuscular diseases such as Duchenne muscular dystrophy by systemic administration of AAV vectors requires production of clinical-grade vector batches at very large scale. As an example, a phase-I/II clinical trial for a local-regional treatment of DMD using the AAV8-exon skipping approach would require 1-4x10E16 total vector genomes (vg). Traditional, cell transfection-based technology is inadequate to produce such large amounts of vector. Today, a standard production process at a 200L scale permits the production of up to 5x10E15 vg per run, meaning that several runs will be required for the manufacturing of the AAV necessary for the phase I clinical trial. In parallel to this development and scale-up, the required analytical and QC methods had been developed and/or adapted to this specific technology for releasing of large scale GMP-compliant vector batches. The talk will present some approaches to intensify the actual production scheme.
New Investigator Town Hall Gathering 5:45 PM - 6:45 PM Room: 203 AB
ChairMatthew D. Weitzman, PhD
John J. Rossi, PhD Engaging Young Investigators as ASGCT Active Participants and Molecular Therapy Contributors The long term success of any scientific organization depends upon its ability to recruit and engage young investigators. ASGCT provides an outstanding opportunity for young investigators to network with other scientists whom they might not ordinarily interact with via the annual meeting and the interactive Web site. The Society also has two journals (and more in the planning) which provide a forum for young investigators to publish their gene and cell therapy related research findings. This presentation will focus on ways for junior investigators to become involved with the running of the Society. The presentation will also navigate you through the process of manuscript submission, review and decision making for the Society journals Molecular Therapy and Molecular Therapy Nucleic Acids.
Robert W. Doms, MD, PhD So you want to be the Boss? Successfully completing a PhD or MD and subsequent postdoctoral fellowship are the first steps for a career in research. The next step to establishing your own laboratory and building your research program is one of the most challenging transitions in an academic career. This presentation will provide advice for young investigators embarking of this transition. The speaker will cover strategies that will help investigators to navigate the tasks of obtaining and negotiating a faculty position, defining your research mission, staffing your lab, getting funded, and developing an academic career.
Terry R. Bishop, PhD Grant Opportunities from the NIH NIH is committed to maintaining the “pipeline” open for investigators just entering a research career. Programs that are specific for new investigators will be discussed. In addition, new policies affecting success rates for R01 applications from new investigators will be discussed. And finally, several resources will be provided to assist Early-Stage Investigators.
Andrew M. Scharenberg, MD Building a Career in Cell and Gene Therapy Successful cell and gene therapies require the participation and close collaboration of individuals with expertise in basic science, technology development, industrial biotechnology, and patient care. Consequently, the field of cell and gene therapy offers diverse avenues to building a rewarding career. The speaker will discuss his perspective on the career opportunities available in the field, provide some general rules for how to successfully get involved, and attempt to highlight both exciting future directions and potential challenges.
South American Attendee Reception 7:45 PM - 9:15 PM Room: Marriott JWs
