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Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS

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Annual rept. 1 Aug 2014-31 Jul 2015

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Amyotrophic lateral sclerosis ALS is characterized by the progressive degeneration of motor neurons leading to skeletal muscle atrophy, paralysis, and the death of patients within 2 to 5 years of disease onset. Currently, ALS cannot be prevented and disease progression can be only minimally delayed. Many previous reports have shown that glial cell line-derived neurotrophic factor GDNF ameliorates certain aspects of the disease in a number of different animal models of ALS. Despite many encouraging results, a strategy aimed at delivering GDNF has yet to be used in a clinical trial for ALS. Recent research and phase III clinical trial successes using adeno-associated virus AAV as a therapeutic tool have led to a renewed interest in a gene therapy approach for various disorders of the nervous system. To date, no clinical trial for ALS has yet exploited a gene therapeutic strategy, which prompted us to investigate this approach for ALS. Here, we have chosen to use an AAV based gene therapy approach as a straightforward strategy to promote GDNF production in muscles. Hypothesis Intramuscular AAV5-GDNF injection will ameliorate motor neuron function in the SOD1G93A rat model of ALS. Objectives To perform crucial and extensive pre-clinical studies to enable an investigational new drug IND application with the Food and Drug Administration FDA for the approval to move the use of intramuscular GDNF delivery by AAV5 into humans affected by ALS. Findings Using a combination of DOD, ALS Association and institutional funding we have investigated the potential of intramuscular AAV1, AAV5, AAV26 and AAV9 encoding GDNF as a therapeutic approach to ALS. In all cases intramuscularly administered AAV encoding GDNF did not have an overt beneficial effect on motor neuron function. Alternative treatment We propose to pursue the project using an ex-vivo gene therapeutic approach based on the intramuscular transplantation of mesenchymal stem cells MSC secreting GDNF.

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  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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