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CTGTAC #41 National Toxicology Program Proposed Study Design: Model for Retroviral-Mediated...
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CTGTAC #41
National Toxicology Program Proposed Study Design:
Model for Retroviral-Mediated Model for Retroviral-Mediated Insertional MutagenesisInsertional Mutagenesis
Carolyn A. Wilson, Ph.D.Division of Cellular and Gene Therapies, Office
of Cellular, Tissue, and Gene [email protected]
Overview of FDA Presentation
• Why consider performing the proposed study?
• What are the study goals?• What are the goals for today’s
meeting?
Gammaretroviral-Mediated Endogenous Gene Activation
Distal Gene Activation
Read-throughTranscription
Psi (Internal Promotor) Transgene LTR LTRLTR LTRLTR
U3 R U5U3
DysregulatedGene Expression
Tumorigenesis
Gene Disruption
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)
X-SCID Gene Therapy* Increased
Transduction Rates THERAPEUTICBENEFIT
In vivo Selective Advantage
+INCREASED
RISK
+
*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.
CRITICAL PATH:CRITICAL PATH:Success of retroviral vectors will be Success of retroviral vectors will be
limited by potential for limited by potential for tumorigenesistumorigenesis
Actu
al R
isk
Therapeutic
Benefit
A valid preclinical model is needed to assess
the relative risks of vectors modified to reduce the likelihood of tumorigenesis
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
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
Leukemias Observed in Mouse Model of Retroviral Vector Hematopoietic Stem Cell
Transduction
Evi-1
Leukemic Clone
AML-like diseaseLi, et al, Science, 2002
Additional relevant preclinical studies will be presented by Chris Baum
Control
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
Goal for Today: Discussion of FDA Questions
1. 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.
FDA Question #22. 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.
FDA Question #33. 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.