An intramuscular gene therapy trial in LGMD2D to replace the human alpha-sarcoglycan gene (hSGCA) delivered by rAAV1 under control of a muscle creatine kinase promoter was recently completed. Gene expression was observed for as long as 6 months. No adverse effects were encountered. That study provided the foundation and the impetus to move forward with a vascular delivery trial. In the laboratory we have established that rAAV.rh.74 can effectively deliver hSGCA to specific muscle groups through the femoral artery in the non-human primate. Delivery is achieved with the extremity isolated from the systemic circulation using a temporary ligature proximal to the site of infusion and a blood pressure cuff at the knee. Containment of virus to promote safety is an important consideration for the first vascular gene delivery trial in muscular dystrophy. The method is safe, effective and reproducible. We have presented these findings to the FDA (pre- IND meeting) and they were receptive to this approach. In addition we have obtained funding (MDA) for the toxicology-biodistribution study that is currently underway that will lead to an IND, permitting entrie to the clinical trial. Our Center holds two INDs for muscular dystrophy gene therapy and we have a devoted staff that is self sufficient and capable of preparing all of the necessary regulatory documents (IND, RAC, IRB) for the clinical trial. The current grant proposal is divided into two aims.
Aim1 is the preparation of vector for the clinical trial (self-complementary rAAV.rh.74.tMCK.hSGCA). Nationwide Children's Hospital is uniquely positioned to make vector in a timely manner because a vector manufacturing facility has been established in the Center for Gene Therapy within the Children's Hospital Research Institute. Production of clinical grade vector can start immediately upon receiving funds awarded by this grant proposal.
Aim 2 calls for the performance of a dose-escalation trial in LGMD2D patients. The Center for Gene Therapy at NCH is highly qualified and uniquely experienced in gene therapy trials. The proposed study will be a dose escalation trial of rAAV.rh.74.tMCK.hSGCA delivered through the femoral artery. Targeting the quadriceps muscle will provide a means for improving muscle strength and thereby prolong ambulation. Both limbs will be perfused within a single treatment episode, an approach approved by the FDA in our pre-IND meeting. Three patients will receive low dose vector (6x1011 vg/kg) and three others will receive the high dose (2x1012 vg/kg). The immune response to virus and transgene will be fully studied as we have done in prior gene therapy studies. The outcome measures proven to be satisfactory and used extensively in our clinical trials program will determine efficacy of this approach.

Public Health Relevance

Currently there is very limited treatment for muscular dystrophy. Supportive and respiratory care have helped prolong life but quality of life is very limited. We have found a way to restore the missing gene in limb-girdle muscular dystrophy using a virus to deliver the defective gene through the circulation. In this study we will replace the alpha-sarcoglycan gene in the proximal leg muscles in patients with LGMD2D. The objective will be to prolong ambulation.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project--Cooperative Agreements (U01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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Nationwide Children's Hospital
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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