Intrathecal Gene Therapy Expressing IGF-1 for Amyotrophic Lateral Sclerosis

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disorder striking about 1 person in 40,000 each year. Individuals with ALS exhibit rapid loss of muscle control, muscle atrophy, and death due to respiratory failure. The cause of ALS is the progressive denervation of muscle by motor neurons. There is currently no cure for this disease, and the only approved therapy has a very modest effect on the disease progression. Clearly, there is a pressing need for more effective therapies. One possible route would be to use neuroprotective factors which, due to their general mode of action, may have utility in other neuromuscular disorders as well. Our long-term objective for this project is to develop gene therapy for ALS. Previous studies have investigated the use of neuroprotective factors. These molecules, such as insulin-like growth factor 1 (IGF-1) provide anti-apoptotic signals for motor neurons as well as promoting neurite outgrowth. These molecules seemed promising in animal studies. However, clinical trials demonstrated that scaling the dose to humans poses daunting challenges. A more effective approach might be to use gene therapy to allow the patients' own cells to produce the therapeutic factor. Several studies, including our own, have shown this approach has merit. However, these studies used techniques that have not scaled up well in larger animal models. Intraparenchymal injection into the spinal cord results in only localized transgene expression and thus would require an unreasonably large number of injections in humans. Retrograde transport in motor neurons of vector injected into muscle was also effective in a rodent model of ALS, but again would likely have limited clinical applicability due to the muscle mass that would need to be injected. In this proposal we will investigate efficacy of intrathecally administered gene therapy expressing IGF-1 in the SOD1-G93A rat model of ALS. In Specific Aim 1, we show that our gene therapy can promote motor neuron survival and protect the integrity of neuromuscular junctions. In addition we will show that this therapy attenuates the activation of astrocytes and microglia that helps contribute to th destruction of motor neurons. Furthermore, we will investigate the possibility that motor neurons can develop tolerance to elevated levels of IGF-1, a phenomenon that could limit the effectiveness of this therapy long-term. In Specific Aim 2, we will show that the improvements found in Aim 1 translate into improved motor function and increased life span. SOD1 rats will be evaluated using the grip strength, rotarod, and open field tests to evaluate several aspects of motor function. In addition, life span, age at disease onset, and the rate of disease progression will be measured to show efficacy. This study will provide the proof-of-principle data necessary to support future clinical trials of this approach.