OCTGT Site visit, September 29, 2005. Research Management, Priorities, and Accomplishments. Suzanne Epstein, Ph.D. Associate Director for Research, OCTGT. The Challenge. OCTGT formed to regulate cell therapies, gene therapies, tissues, other novel products Key issues include:
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Research Management, Priorities,
Suzanne Epstein, Ph.D.
Associate Director for Research, OCTGT
Key issues include:
available in-house for consultation in relation to regulatory work
Expertise identified as needed for future product review:
Build on existing programs
uses impact factors and authorship weighting (limitations of impact scores vs. quality, relevance).
Anticipate needs, as well as addressing current problems:
not only individual products
sponsors, to advance the entire field
Public Health Issues and Regulatory Challenges:
Fatal pulmonary edema
Smith et al. (2004). Molecular Therapy 9:932
Smith et al. (2004). Gene Therapy 11:431What happens in animals with liver disease?
Cirrhotic rats have a severe pulmonary reaction
after i.v. adenovirus vector
Major issues: controlling growth and differentiation of cells, product characterization, immune rejection
cellular therapy products
after administration to the patient. Thus, cell survival is
a Critical Path efficacy question
screening to evaluate interacting genes and identify
new predictors of cell survival and product efficacy
Low BMP signaling
caspase 3, activated JNK pathway
rvInactivation of Notch2 Results in Loss of Notch2+ Myocardial Cells and Hypoplastic Hearts
Model: mice in which Notch2 can be turned on or off in specific tissue
Notch2+ cells are blue
vs = ventricular septation defect
Correct tissue formation requires Notch2 signaling
Major issues: interactions yielding proper tissue structure and function.
Strategies to address them - Projects:
Expression of growth factors and the enzymes that activate them overlaps only at anatomic boundaries
Related future work relevant also to cell therapies:
Major issues: transmission of infectious agents between species, immune rejection.
and species tropism
agents, especially in immune-suppressed patients
Wilson, C., et al., J. Virol., 1998. 72(4):3082.
PERV-A/CInfection of Human Cells Determined by Envelope
Portion of PERV-C envelope
differing from PERV-A by
9 amino acids greatly reduces
infection of human cells
Gemeniano, et al, Virology, In Press
MAJOR ISSUES: Product characterization, including tests for identity, purity, potency; animal models, markers for monitoring and immunogenicity.
Public Health Impact and Regulatory Challenge:
Expression of receptor
Mouse model of metastatic ovarian cancer
Uses of gene expression microarray
and flow cytometry
High throughput screening provides
detailed information. Can be used for
Identify markers of stem cell state
Outcome: CBER/NIH/Industry scientists identified and characterized common “stemness” genes in 6 stem cell lines. Bhattacharya, Blood: 103, 2956-2964, 2004
Intensity, cell subsets
NIST Microbead Standard
Retroviral reference material
Adenovirus reference material
LTR gag pol env LTR
External RNA spike-in controls for microarray and RT-PCR
Outcome: Sensitive, consistent testing facilitates progress, provides savings
regulatory challenges and opportunities
importance and address them.
development, inform regulatory decisions and policy.
We welcome questions and comments from the Committee.