The goal of this proposal is to design, test, and produce a recombinant adeno-associated viral (AAV) vector carrying a functional mini-dystrophin gene which will be extensively studied in vivo for therapeutic efficacy as well as long-term safety in animal models. The clinical grade vector will be produced in the final year for a Phase I gene therapy safety trial for Duchenne muscular dystrophy (DMD). This proposal is highly integrated, involving scientists in both basic research and clinical studies, with the objective of generating an optimized AAV vector in five years for a Phase I safety trial in DMD patients. The design, test and production of the gene vectors and the pre-clinical safety studies, as required by FDA, will be carried out at the University of Pittsburgh in collaboration with other institutions. A parallel study that is equally important for the success of the clinical trial, but through a different funding mechanism outside this proposal, will be conducted by a team led by Dr. Jerry R. Mendell at the Ohio State University, where a DMD patient cohort will be characterized at the pathological, immunological and molecular levels for future recruitment. To successfully execute this challenging translational research project, we plan to accomplish five Specific Aims. The first three Aims will be devoted to optimization of mini-dystrophin genes, selection of a small but strong muscle-specific promoter, and the investigation of gene delivery methods. The last two Aims will concentrate on preclinical vector toxicology study and clinical grade AAV vector production under the GMP conditions. The success of this grant will lead to the IND filing and RAC submission of the DMD gene therapy protocol.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS046546-01A2
Application #
6832680
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Porter, John D
Project Start
2004-09-01
Project End
2008-06-30
Budget Start
2004-09-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$358,453
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Bilbao, Roberto; Reay, Daniel P; Li, Juan et al. (2005) Patterns of gene expression from in utero delivery of adenoviral-associated vector serotype 1. Hum Gene Ther 16:678-84
Wang, Zhong; Zhu, Tong; Qiao, Chunping et al. (2005) Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol 23:321-8
Zhu, Tong; Zhou, Liqiao; Mori, Satsuki et al. (2005) Sustained whole-body functional rescue in congestive heart failure and muscular dystrophy hamsters by systemic gene transfer. Circulation 112:2650-9
Ye, Xiaojing; Zhu, Tong; Bastacky, Sheldon et al. (2005) Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno-associated virus-mediated gene transfer. Arthritis Rheum 52:3975-86