Program Schedule
(This program is subject to updates/changes.)
This session will introduce three of the most popular versions of retroviral delivery systems, for which an increasing repertoire of strains and genera becomes available: gammaretroviral (based on murine leukemia virus), lentiviral (based on human immunodeficiency virus type 1) and spumaviral (based on “human” foamyvirus). They share the default aspects of the retroviral life cycle: receptor-mediated uptake of an enveloped particle, reverse transcription of a plus-stranded mRNA, and more or less random integration of double-stranded DNA following nuclear uptake of the preintegration complex. However, we will also discuss important differences in efficiency and biosafety related to viral origin and vector architecture.
Room: 263/267
Chair:
Christopher Baum, MD
Speakers:
Christopher Baum, MD - Retrovirus Vectors: We Are Family!
Luigi Naldini, MD, PhD - Lentiviral Vectors: Challenges and Expectations
David W. Russell, MD, PhD - Foamy Virus Vectors
Nonviral gene therapy approaches may be simpler and safer than those using viral vectors. The challenges of non-viral gene therapy involve 1) development of vectors that provide long-term expression of therapeutic genes, and 2) development of suitable methods to deliver vector DNA to target cells. This session will examine the latest integrating and non-integrating vectors for achieving long-term gene expression and will describe current physical and chemical methods for DNA delivery.
Room: 260/264
Chair:
Michele P. Calos, PhD
Speakers:
Michele P. Calos, PhD - Integrating and Non-integrating Plasmids for Non-viral Gene Therapy
Daniel Scherman, PhD - In Vivo Electrotransfer of Plasmids or Synthetic Nucleotides: Basic Concepts and Potential Therapeutic Applications
Dexi Liu, PhD - What Constitutes a Better Synthetic Vector?
In vivo delivery of genes for therapeutic purposes and vaccines induces immune responses directed both against the vector as well as the gene-product. The goal of this educational session is to provide an overview of the role of immune responses in strategies for development of vector systems for gene therapy and vaccines. The overview of the immune response will include innate immunity, antigen processing and presentation, lymphocyte activation, induction of effecter responses and regulation of the immune responses. There will be a presentation and discussion on the use of gene transfer to induce tolerance to therapeutic or transplant antigens. Several exciting new approaches involving mechanisms of deletion, energy, or suppression will be discussed. In addition experiences of immunologic factors influencing efficacy, and safety in clinical trials with viral vectors will be reviewed.
Room: 120/124
Chair:
Maria Grazia Roncarolo, MD
Speakers:
Maria Grazia Roncarolo, MD - The Role of Regulatory T Cells in Suppressing Immune Responses to Transgenes and Inducing Immune Tolerance
Jacques Banchereau, PhD - Dendritic Cells: Controllers of Immune Responses
This session will discuss FDA’s perspectives on what investigator/ sponsors can do to help move the field of gene therapy forward and get products to licensure. FDA will discuss what is the most efficient way to establish safety and efficacy, as well as what type of preclinical studies should be performed prior to initiation of clinical trials. Questions regarding the conduct of exploratory and confirmatory clinical trials will be discussed. FDA will also discuss why product characterization is important during early product development. These issues will be discussed as a way of explaining how the academic investigator can play a role in partnering with industry to help bring gene therapy products to licensure.
Room: 265/266
Chair:
Stephanie Simek, PhD
Speakers:
Andrew Byrnes, PhD - Common Challenges in the Development of Gene Therapy Products
Mercedes Serabian, MS, DABT - Preclinical Considerations Beyond Phase 1
Daniel Rosenblum, MD - How to Make Optimal Use of the Approval Process
Gene Therapy projects require expression of an exogenously introduced therapeutic gene. In The 1995 Orkin and Motulsky report identified inadequate knowledge of vector components necessary to maintain adequate expression of the therapeutic gene as a major fault in the field. Over the last 10 years, a significant amount of effort has been invested toward the development of optimized expression cassettes that provide sustained, high – level expression of therapeutic proteins in relevant disease models with viral and non – viral vectors. This session will provide guidance for the development of expression cassettes yielding high level, sustained expression of a desired therapeutic protein. The three presentations will provide (1) an overview to expression cassette design for viral and non – viral vectors, with a focus on using viral and house – keeping promoters for highest level of gene expression initially following gene transfer, (2) strategies that have been successfully used to provide sustained, high level tissue – specific expression, and (3) vector strategies that optimize protein expression through the use of optimal intron configuration and mRNA splicing, mRNA stability elements and translation initiation site configuration. A question and answer session will follow.
Room: 123/127
Chair:
Mitchell Finer, PhD
Speakers:
Mitchell Finer, PhD - Expression Cassette Design - 20 Years in 20 Minutes
Carol H. Miao, PhD - Establishment of High-Level and Tissue-Specific Gene Expression Cassettes
Thomas J. Hope, PhD - Post Transcriptional Regulation in Gene Expression Vectors
Cancer has been a target application for numerous gene therapy trials. Recent advances in the use of oncolytic viruses, the type of anticancer transgenes employed for biologic effects and the effects of the immune system will be discussed. The understanding of these topics will facilitate improved applications in human trials.
Room: 240 Complex
Chair:
E. Antonio Chiocca, MD, PhD
Speakers:
E. Antonio Chiocca, MD, PhD - HSV Oncolytic Viruses
Glen Barber, PhD - VSV as an Oncolytic Vector: Mechanisms of Action
Noriyuki Kasahara, MD, PhD - Retrovirus Vectors for Cancer Gene Therapy: Oncolytic, Anti-angiogenic, and Immunotherapeutic Strategies
The goal of the Adenovirus Education Session is to survey the current state-of-the-art in our development and use of adenovirus gene transfer vectors. The session will begin with a discussion of the molecular biology of adenovirus including the production of replication –deficient vectors and packaging cell lines, the benefits and deficits of deletions of subsets or all the viral genes in the vector, the logic behind conditionally replicating adenoviruses, and variations relating to the Transgene expression cassette. The second topic of discussion will address the efficiency with which adenovirus interacts with target cells to deliver its genome to the nucleus. This discussion will include the basic infection pathway, altered vector tropism, variables relating to target cell type and physiology, and in vivo vector trafficking. The final topic of the session will be the interaction between adenovirus and the immune system including innate immunity, acquired immunity, and strategies for circumventing immune system barriers.
Room: 263/267
Chair:
Philip L. Leopold, PhD
Speakers:
Neil R. Hackett, PhD - Molecular Biology of Adenovirus Vectors
Philip L. Leopold, PhD - Cell Biology of Adenovirus Infection: Subcellular Mimicry
James M. Wilson, MD PhD - Immunology of Adenoviral Vectors
This session will describe design features and production features, plus experimental and therapeutic uses of recombinant oncolytic, replication defective and amplicon vectors derived from herpes simplex virus type 1. Oncolytic vectors are designed for treatment of cancer based on targeted delivery and selective virus replication in tumor cells. Clinical trials using these vectors for brain tumors will be described. Replication defective viruses deleted for essential viral functions have been engineered for peripheral nervous system applications since they naturally persist in sensory nerves following local delivery to the skin. Amplicon vectors incorporate no viral genes and can include up to 150 kb of genetic information, including complete genes, self-contained regulatory elements and AAV genome integrating components. These vectors provide versatile tools for systematic genetics and therapeutics.
Room: 260/264
Chair:
Xandra Breakefield, PhD
Speakers:
Xandra Breakefield, PhD - Mega-multi Capacity HSV Amplicon Vectors
Joseph C. Glorioso, PhD - HSV Gene Vectors for Treatment of Pain and Neuropathy
E. Antonio Chiocca, MD, PhD - HSV Vectors for Chemotherapy Delivery
The ability to regulate the timing and level of transgene expression opened new avenues in basic research applications and might become prerequisites in future clinical settings. Several gene regulation systems have been developed and successfully incorporated into viral and non-viral gene delivery systems. The session will begin with a general overview on the characteristics common to the various gene expression regulating systems. The following parts of the session will focus on the most common gene regulatory systems including the tetracycline, ecdysone, and the dimerizer systems. The last part of this session will cover new developments in regulating siRNA expression cassettes.
Room: 265/266
Chair:
Tal Kafri, PhD
Speakers:
Tal Kafri, PhD - General overview on transgene regulation with special emphasis on the tetracycline gene regulatory system
Francesco Galimi, MD, PhD - Regulation of Transgene Expression: Vector Designs and Applications
Jakob Reiser, PhD - Knockdown Control: Practical Approaches to Regulating shRNA Expression
The goal of this session is to acquaint participants with training and career development application mechanisms and the review process at the NIH. Staff will give advice on what contributes a successful grant application and how to pick the right mechanism depending on the applicant’s expertise and education. There will be an opportunity for questions during the presentations and NIH staff will be available for individual questions. This session is intended for new investigators but should be informative for any investigator planning to submit an NIH grant application.
Room: 120/124
Chair:
Sonia I. Skarlatos, PhD
Speakers:
Sonia I. Skarlatos, PhD - Research Training and Career Development Programs
Steven J. Zullo, PhD - Grant Review in the CSR
Arun Srivastava, PhD - Writing and Reviewing NIH Grants: A Personal Odyssey
This educational session will focus on applications, methods and strategies for gene transfer to muscle tissue. The first lecture will give an overview of viral vectors for muscle gene transfer in vivo. The advantages and disadvantages of a variety of commonly used vectors with examples of their application will be discussed. The second lecture will focus on non-viral methods for gene transfer to muscle, which is uniquely suited for uptake of non-viral vectors. The final topic will be on ex vivo methods for gene transfer and appropriate vectors for transducing stem cells.
Room: 123/127
Chair:
Jeffrey Chamberlain, PhD
Speakers:
Jeffrey Chamberlain, PhD - Viral Gene Transfer
Jon Wolff, MD - Non-Viral Gene Transfer
Giuliana Ferrari, PhD - Cell Therapy for Muscular Dystrophy
The goal of this session is to highlight scientific, technological and logistical aspects that bear on the successful translation and clinical implementation of gene therapy research. This year’s session will focus on the severe combined immune deficiencies (SCID). The faculty will discuss their experience with adenosine deaminase (ADA) deficiency, X-linked SCID and Wiskott-Aldrich syndrome, with emphasis on the strategic choices they have made and the hurdles they have confronted on issues such as vector/promoter selection, small vs. large animal models, vector production, infrastructure development, protocol approval, patient selection and recruitment, quality assurance and regulatory oversight.
Room: 230/231
Chair:
Michel Sadelain, MD PhD
Speakers:
Donald B. Kohn, MD - ADA-Deficient SCID: Pathogenis and Treatments
Marina Cavazzana-Calvo, MD, PhD - Severe Combined Immunodeficiency: Disease Models for New Therapetical Approaches
Arthur Nienhuis, MD - Development of Gene Therapy for Wiskott-Aldrich Syndrome
Novel adenovirus and adeno-associated virus vectors have been developed recently, which enable the delivery of transgenes into target cells and tissues with efficiency and specificity. Application of these novel vectors in the delivery of therapeutic genes to treat inherited disorders as well as acquired diseases like cancer will be discussed.
Room: 260/264
Chair:
Savio L.C. Woo, PhD
Speakers:
Andre Lieber, MD, PhD - Gene Transfer Vectors Based on B-group Adenoviruses
David T. Curiel, MD, PhD - Targetable/Injectable Adenoviral Vectors for Cell-specific Gene Transfer In Vivo
Guangping Gao, PhD - Efficient Gene Transfer Vectors Based on Novel Primate AAVs
The goal of the AAV Education Session is to provide the community not only with a general understanding of this popular vector system, but to integrate this into a broader awareness of expectations when using these vectors in vitro and in vivo. Three topics will be discussed in this session. The first speaker will begin with a general background of AAV biology including a discussion of the molecular fate of recombinant genomes in vitro and in vivo. The second topic will concentrate on structural differences between AAV serotypes and how those differences can be utilized to improve the vector delivery. The final topic will focus on applications of AAV serotype delivery to specific target organs including performance comparisons between different serotypes.
Room: 263/267
Chair:
Joseph Rabinowitz, PhD
Speakers:
Joseph Rabinowitz, PhD - Exploring the Structure and Function of the AAV Virion
Xiao Xiao, PhD - Recent Progress in AAV Vector Development
K. Reed Clark, PhD - Wild-type and Recombinant AAV Biology - An Update
RNA interference refers to a cells natural ability to silence gene expression using short interfering RNAs (siRNAs). Inhibitory RNAs are derived from larger precursors transcribed from the genome, or introduced into cells artificially. The power of RNAi has recently been harnessed by the bench scientist to selectively inhibit the expression of diverse gene products to ascertain biological function, or as therapeutic tools for silencing pathogenic protein expression. This session will provide an overview of the protein complexes involved in RNAi, and will also illustrate various methods to accomplish RNAi in cells, tissues and animals.
Room: 240 Complex
Chair:
Beverly L. Davidson, PhD
Speakers:
Beverly L. Davidson, PhD - RNA Interference
John J. Rossi, PhD - The Long and Short of RNAi
Michael McManus, PhD - Developmental and Post-developmental Phenotypes of MicroRNA Ablation in the Mouse
In this session the three speakers will address specific issues pertaining to gene transfer in the nervous system. The broad goals are to convey to the audience the anatomic, immunologic and development aspects of the nervous system that are unique as a target for gene therapy. Dr. Fink will highlight the peripheral nervous system development, anatomy, function and disease related dysfunctions. Dr. Maria Castro will address neural immune interactions, locus of antigen presentation and consequences for gene transfer. Dr. Federoff will touch on special problems encountered in the translation of preclinical gene therapy. He will also briefly highlight issues related to the development of in utero CNS gene therapy.
Room: 230/231
Chair:
Howard J. Federoff, MD, PhD
Speakers:
Howard J. Federoff, MD, PhD - Translational Considerations for CNS Gene Therapy
David J. Fink, MD - Gene Transfer to DRG for Treatment of Neuropathy or Chronic Pain
Maria Castro, PhD - Regulated, Long Term Therapeutic Gene Expression for Neurological Gene Therapy
Pharmacokinetic analysis translates the disposition characteristics of macromolecules into quantitative parameters that can be used for direct comparison of medicinal agents as well as with physiological parameters such as blood flow and the rate of cellular endocytosis. Careful collection and experimental analysis of biological samples as well as theoretical development of appropriate mathematical models are necessary for accurate prediction of drug disposition and comparison of treatment regimens. This session, designed for the bench scientist and the clinician alike, will discuss basic pharmacokinetic concepts, methods for modeling, study design, data analysis, population kinetics and their application to gene delivery systems.
Room: 265/266
Chair:
Maria A. Croyle, PhD
Speakers:
Maria A. Croyle, PhD - Pharmacokinetics Made Easy
Sally Choe, PhD - Bridging Preclinical and Clinical Pharmacokinetics in Gene Therapy
This session will give the fundamentals as well as updates about Gene-based vaccines. The technology, immune mechanisms, and second generation advances describing new delivery systems and the use of adjuvants will be presented. An overview of clinical and research applications will be described.
Room: 120/124
Chair:
Margaret A. Liu, MD
Speakers:
Margaret A. Liu, MD - Gene-based Vaccines: An Overview
Jeffrey Ulmer, PhD - Toward the Development of an Effective DNA Vaccine for Humans
Hildegund CJ Ertl, MD - Adaptive Immune Responses to Viral Vectors
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