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首页> 美国政府科技报告 >Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS.
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Muscle-Derived GDNF: A Gene Therapeutic Approach for Preserving Motor Neuron Function in ALS.

机译：肌源性GDNF：一种保持肌萎缩侧索硬化运动神经元功能的基因治疗方法。

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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 I/II 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, AAV2/6 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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