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CTGTAC #41 National Toxicology Program Proposed Study Design: Model for Retroviral-Mediated Insertional Mutagenesis

CTGTAC #41 National Toxicology Program Proposed Study Design: Model for Retroviral-Mediated Insertional Mutagenesis. Carolyn A. Wilson, Ph.D. Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies carolyn.wilson@fda.hhs.gov. Overview of FDA Presentation.

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CTGTAC #41 National Toxicology Program Proposed Study Design: Model for Retroviral-Mediated Insertional Mutagenesis

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  1. CTGTAC #41National Toxicology Program Proposed Study Design: Model for Retroviral-Mediated Insertional Mutagenesis Carolyn A. Wilson, Ph.D. Division of Cellular and Gene Therapies, Office of Cellular, Tissue, and Gene Therapies carolyn.wilson@fda.hhs.gov

  2. Overview of FDA Presentation • Why consider performing the proposed study? • What are the study goals? • What are the goals for today’s meeting?

  3. Psi (Internal Promotor) Transgene LTR LTR LTR LTR LTR U3 R U5 U3 Read-through Transcription Dysregulated Gene Expression Distal Gene Activation Tumorigenesis Gammaretroviral-Mediated Endogenous Gene Activation Gene Disruption

  4. Retroviral Vectors and Tumorigenesis • Wildtype Retroviruses • Used as models to study tumorigenesis • Used as models to induce genetic aberrations • Acknowledged risk in use of retroviral vector-mediated gene therapy • In absence of replication, finite number of sites for genomic integration (reduced risk)

  5. THERAPEUTIC BENEFIT + + In vivo Selective Advantage INCREASED RISK X-SCID Gene Therapy* Increased Transduction Rates *Cavazzana-Calvo, M., et al. 2000. Science 288:669-72. Hacein-Bey-Abina, et al. 2002. New England Journal of Medicine 346:1185-1193. Hacein-Bey-Abina, S., et al. 2003.. N Engl J Med 348:255-6.

  6. CRITICAL PATH: Success of retroviral vectors will be limited by potential for tumorigenesis Therapeutic Benefit Actual Risk A valid preclinical model is needed to assess the relative risks of vectors modified to reduce the likelihood of tumorigenesis

  7. Previous CTGTAC Advice • Investigators should be encouraged to explore alternative retroviral vector structures to reduce the risk of tumorigenesis, for example: • Deletion of U3 • Insulator elements • Suicide genes • Alternative vectors should be adequately tested in animal models

  8. Considerations in choice of preclinical models • In vitro genomics that map vector insertion sites do not show biological effect • Large animal studies are limited by • study size that is feasible • cost of long-term observation • Rodent Studies • Allow analysis for biological effects of vector insertion • Allow use of large study size • Model should mimic human clinical studies • Target cells used for retroviral vector transduction • Measurable rate of tumorigenesis in animals

  9. Leukemias Observed in Mouse Model of Retroviral Vector Hematopoietic Stem Cell Transduction Leukemic Clone Evi-1 Control AML-like disease Li, et al, Science, 2002 Additional relevant preclinical studies will be presented by Chris Baum

  10. Goals of Proposed NTP Study • Develop and assess the sensitivity of a preclinical model for assessing the risk of retroviral vector-mediated insertional tumorigenesis • 50 mice per group of primary recipients • 2 secondary recipients/asymptomatic primary • Assess the effect of vector dose on tumor frequency • Assess the effect of deleting U3 from the LTR Study design will be presented by Rick Irwin

  11. Goal for Today: Discussion of FDA Questions • Please comment on the general scientific approach proposed to evaluate a mouse bone marrow transplantation model for its feasibility to assess pre-clinical safety of retroviral vectors.

  12. FDA Question #2 • The FDA/NTP partnership may have opportunities to explore other models in the future. Please comment on future studies that may be useful to assess retroviral vector safety. a. Specifically, please comment on whether the use of an in utero gene transfer model, such as that used by Themis, et al*, should be examined through the NTP program for its potential as a toxicology model for assessing lentivirus vector tumorigenicity. *Themis, M., et al., Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol Ther, 2005. 12(4): p. 763-71.

  13. FDA Question #3 • If time permits, we would welcome your comments on the following: a. Possible toxicology models of other cellular or gene therapies that would be useful to study through NTP. b. The use of NTP as a resource for development of toxicological testing models for novel therapies.

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