Currently, proof-of-principle studies have established that gene replacement therapy represents a promising means of treatment for Duchenne muscular dystrophy (DMD). We have moved forward in a clinical phase I safety gene therapy trial for this disease by intramuscular delivery of an rAAV mini-dystrophin gene. It is acknowledged throughout the field that vascular delivery, reaching many muscle groups, is our best hope for improving patient function. In preliminary discussions with the FDA in preparation for this U54, we were encouraged to move forward with gene delivery through the circulation, being mindful of potential safety concerns. Our current project takes these considerations into account. We have found in preliminary studies that rAAVS can deliver micro-dystrophin efficiently to muscle in the mdx mouse. Further, we have data that predicts that this AAV serotype can cross species lines with delivery of a transgene to a large animal species. This sets the stage for our current proposal, integrating safety and efficacy concerns of vascular delivery. Our plan to bring this to IND and a phase I safety trial for vascular delivery is as follows: The first goal for this project (AIM1) is to establish that the micro-dystrophin transgene that we designed (based on the best information from the literature) can functionally improve dystrophic muscle. For our current IND we used an isolated muscle in the mdx mouse to prove functional efficacy and we will follow this example in this proposal. For our second goal (AIM 2) we will deliver the rAAVS.micro-dystrophin to the rhesus macaque. There have been many issues raised regarding the immunogenicity of both AAV and the cargo it carries. The rhesus macaque permits us to address all of these issues in an environment that closely simulates a clinical trial. Two concerns are at hand, safe passage of virus to achieve transduction and safety to the patient avoiding undesirable spread of virus. Thus, we will deliver our viral construct through a balloon catheter placed in the femoral artery. We will also test appropriateness of immunosuppression regimens for gene delivery using some monkeys with pre-existing immunity to AAV and others naTve to the virus. In the final AIM 3, we will do the toxicology/biodistribution studies in accordance with our discussions with FDA. The information derived from this project will permit us to submit an IND for a phase I safety trial in DMD boys.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS055958-02
Application #
7691708
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$341,924
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Xu, Rui; Jia, Ying; Zygmunt, Deborah A et al. (2018) An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.GALGT2 to Leg Skeletal Muscles in the Rhesus Macaque. Mol Ther Methods Clin Dev 10:89-104
Chicoine, L G; Montgomery, C L; Bremer, W G et al. (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22:338-347
Chicoine, Louis G; Rodino-Klapac, Louise R; Shao, Guohong et al. (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin ?2 surrogates. Mol Ther 22:713-24
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
Malik, Vinod; Rodino-Klapac, Louise R; Mendell, Jerry R (2012) Emerging drugs for Duchenne muscular dystrophy. Expert Opin Emerg Drugs 17:261-77
Rodino-Klapac, Louise R; Montgomery, Chrystal L; Mendell, Jerry R et al. (2011) AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol 709:287-98
Rodino-Klapac, Louise R; Montgomery, Chrystal L; Bremer, William G et al. (2010) Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther 18:109-17
Chandrasekharan, Kumaran; Martin, Paul T (2010) Genetic defects in muscular dystrophy. Methods Enzymol 479:291-322
Mendell, Jerry R; Rodino-Klapac, Louise R; Rosales, Xiomara Q et al. (2010) Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol 68:629-38
Martin, Paul T; Xu, Rui; Rodino-Klapac, Louise R et al. (2009) Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol 296:C476-88

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