1. Georgetown UNIVERSITY Overview of Gene Transfer as an Evolving Neurotherapeutic Modality Howard J Federoff, MD, PhD Georgetown University Medical Center

2. Gene Therapy: a young therapeutic modality 1974: NIH Creates the Recombinant DNA Advisory Committee- The RAC 1988: Dr. Rosenberg proposes first gene marking protocol for tumor infiltrating lympocytes 1990: RAC approves protocol to treat SCID with retrovirus carrying adenosine deamidase 1999: University of Pennsylvania trial with adenovirus results in death of Jesse Gelsinger

3. The Not So O.K. Corral

4. Gene Therapy: a young therapeutic modality 2003: First Parkinson’s disease gene therapy trial proposed

5. New Scientist, 2006 New Scientist 2006

6. Gene Therapy: a young therapeutic modality 2004-2013: Ten trials completed in neurological diseases 2012: First gene therapy product approved- Glybera Pancreatitis

7. “Gene Therapies Will Cure Many a Disease” January 2013

8. Types of Gene Therapy » In vivo  Direct gene transfer into the body or organ » Ex vivo  Gene introduction into cells outside the body and modified cells re- introduced » Somatic cell  Gene transferred into differentiated cell types  Episomal or integrated » Stem cell  Gene transferred into multi-potent cell types  Integrated transgene conveys to daughter cells » Germline  Gene transferred into germ cell  Integrated transgene conveys to differentiated cell types  Integrated transgene conveys to progeny in vivoex vivo Brain

9. C. Sheridan, Nature Biotechnology 29, 121–128 (2011) doi:10.1038/nbt.1769 Clinically Relevant Vectors

10. Contrasting Therapeutic Modalities I Small Molecule » Pharmacokinetics  Define t 1/2  CNS/BBB » Pharmacodynamics  Target engagement  Dose titration to endpoint » Metabolism/Excretion  Pharmacogenomics  Hepatic/renal functions Gene Therapy » Pharmacokinetics  Permanent or long-lived  Modified by host factors  Cell type dependent » Pharmacodynamics  Target engagement variable  Nature of encoded gene  Can be affected by immune responses » Metabolism/Excretion  Highly variable  Dependent on location of expression  Nature of encoded gene

11. Contrasting Therapeutic Modalities II Small Molecule » Delivery  Routes established  Typical widespread bioavailability  Formulation » Toxicity  Can be dose related  Off-target  Contribution of metabolites » Regulatory path  IRB, FDA Gene Therapy » Delivery  Most approaches use vectors  Can effectively localize expression  Often invasive requireing devices  Tropism can affect locus of action » Toxicity  Vector related  Gene product related  On- and off-target  Immunological  Few options with persistent vectors » Regulatory path  IBC, RAC, IRB, FDA

12. The RAC The NIH established the Recombinant DNA Advisory Committee (RAC) on October 7, 1974 because of public concerns regarding the safety of manipulating genetic material through the use of recombinant DNA techniques. The RAC's membership and responsibilities have evolved. A critically important forum for open, public deliberation on the panoply of scientific, ethical, and legal issues raised by recombinant DNA technology and its basic and clinical research applications. Comprised of experts from scientific, medical disciplines and ethicists and members of patient and other lay communities. The Rack

13. Independent Review of the RAC » IOM request by NIH Director:  Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the RAC » Recommendations:  Restrict individual gene transfer protocol reviews to exceptional cases that meet specified criteria  Could not be done by existing bodies (FDA, IRB, IBC) and  New vector, genetic material, delivery methodology  Protocol relies on preclinical data using model of unknown value  Proposed vector, gene construct or delivery method associated with toxicities that are not widely known  Consider integrating oversight for gene transfer and other applications of emerging technologies

15. ASENT Program on Gene therapy » FDA perspective » Delivery » Movement disorders » Neuroimaging » Placebo effect » Panel discussion