Muscular dystrophy is a common genetic disease that affects 1 in 3500 male births annually. The disease is characterized by early muscle hypertrophy followed by muscle degeneration and early death in adolescence resulting from failure of heart and diaphragm muscle. The disease results from mutations that affect expression or function of dystrophin, an important structural component of the subplasma membrane. Currently no treatment is available. The overall goal of the proposed research is to develop gene and cell therapeutic methods for treatment of muscular dystrophy. Clinical, pre-clinical and basic muscle cell development studies are described in which experts in gene transfer, muscle cell biology, animal models of muscular dystrophy and clinical applications are brought together in a manner to achieve the highest level of data sharing, synergy and creative solution finding will be possible. Project 1 (J Mendell) will define clinical end-points and identify cohorts of patient that would participate in a phase I dose escalation safety clinical trial using an AAV gene vector carrying the functional dystrophin minigene delivered to a single skeletal muscle and continue gene therapy clinical trials for limb girdle MD. In Project 2 (X Xiao and J Kornegay), will explore methods for improved AAV-dys gene delivery using the dog model. In Project 3 (J Huard), experiments using muscle stem cells will be carried out using dystrophic mouse models in attempts to achieve muscle delivery of normal muscle derived stem cells to engraft into diseased heart. In Project 4 (J Glorioso), a novel functional genomics approach to identify genes that participate in differentiation of mouse embryonic stem cells toward muscle cell lineages is proposed using HSV gene vector cDNA libraries obtained from muscle derived stem cells. The core programs are designed to directly support the projects in the form of Administration (Core A: J Glorioso and P Robbins), Clinical Vector Production (Core B: J Barranger), a muscular dystrophy dog colony (Core C: J Kornegey) and Imaging (Core D: S Watkins) to provide information on the results of gene transfer in animals and patients. Finally, our center includes a training program for residents interested in gene therapy for muscle disease. We believe this to be a timely and highly innovative proposal which is likely to provide new armroaches to the treatment of muscular dvstrophv.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR050733-06
Application #
7476558
Study Section
Special Emphasis Panel (ZNS1-SRB-M (02))
Program Officer
Nuckolls, Glen H
Project Start
2003-09-30
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$992,626
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Goins, William F; Hall, Bonnie; Cohen, Justus B et al. (2016) Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol 21:93-101
Beckman, Sarah A; Sekiya, Naosumi; Chen, William C W et al. (2014) The cardiac regenerative potential of myoblasts remains limited despite improving their survival via antioxidant treatment. CellR4 Repair Replace Regen Reprogram 2:
Rosales, Xiomara Q; Malik, Vinod; Sneh, Amita et al. (2013) Impaired regeneration in LGMD2A supported by increased PAX7-positive satellite cell content and muscle-specific microrna dysregulation. Muscle Nerve 47:731-9
Sekiya, Naosumi; Tobita, Kimimasa; Beckman, Sarah et al. (2013) Muscle-derived stem cell sheets support pump function and prevent cardiac arrhythmias in a model of chronic myocardial infarction. Mol Ther 21:662-9
Zheng, Bo; Li, Guangheng; Chen, William C W et al. (2013) Human myogenic endothelial cells exhibit chondrogenic and osteogenic potentials at the clonal level. J Orthop Res 31:1089-95
Kornegay, Joe N; Bogan, Janet R; Bogan, Daniel J et al. (2012) Canine models of Duchenne muscular dystrophy and their use in therapeutic strategies. Mamm Genome 23:85-108
Cassino, Theresa R; Drowley, Lauren; Okada, Masaho et al. (2012) Mechanical loading of stem cells for improvement of transplantation outcome in a model of acute myocardial infarction: the role of loading history. Tissue Eng Part A 18:1101-8
Okada, Masaho; Payne, Thomas R; Drowley, Lauren et al. (2012) Human skeletal muscle cells with a slow adhesion rate after isolation and an enhanced stress resistance improve function of ischemic hearts. Mol Ther 20:138-45
Mendell, Jerry R; Rodino-Klapac, Louise; Sahenk, Zarife et al. (2012) Gene therapy for muscular dystrophy: lessons learned and path forward. Neurosci Lett 527:90-9
Xiang, Guosheng; Yang, Qing; Wang, Bing et al. (2011) Lentivirus-mediated Wnt11 gene transfer enhances Cardiomyogenic differentiation of skeletal muscle-derived stem cells. Mol Ther 19:790-6

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