Gene Therapy for Neuromuscular Disorders
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The Ohio State University / OhioLINK
2010
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu12704792732021-08-03T05:58:59Z Gene Therapy for Neuromuscular Disorders Haidet, Amanda M. Biomedical Research <p>Neuromuscular disorders affect thousands in the US including both patients as well as caregivers providing physical, emotional, and financial support. The goal of the studies presented here is to gain a further understanding of the pathogenic disease mechanisms of neuromuscular disorders and develop translational therapies to attempt to treat these diseases.</p><p>The muscular dystrophies are a group of primary muscle disorders leading to muscle wasting and loss of ambulation. Since muscle wasting is a significant cause of disability in many muscle disorders, the aim of our studies was to develop a strategy to increase muscle mass and strength. We hypothesized that inhibiting myostatin, a negative regulator of muscle growth, would lead to increased muscle mass and strength. To inhibit myostatin, we developed an adeno-associated virus (AAV) gene therapy vector to deliver follistatin, an endogenous myostatin antagonist. A single intramuscular injection of AAV-Follistatin was able to increase muscle mass and strength in a mouse model of muscular dystrophy, even when delivered after the onset of muscle degeneration. Next, we tested AAV-Follistatin in the non-human primate since these animals are biologically closer to humans. AAV-Follistatin delivered by intramuscular injection to the quadriceps muscle caused increased muscle size and strength, with no adverse effects in any major organ system. Therefore, AAV-Follistatin represents a promising strategy to treat muscle wasting diseases and warrants further clinical translation. </p><p>In contrast to the muscular dystrophy field, there are currently few promising therapies reaching the clinic for the treatment of Amyotrophic Lateral Sclerosis (ALS). ALS is a neurological disorder caused by the degeneration of motor neurons leading to paralysis and death within 1-5 years of onset. Since there are presently no predictors for who will develop ALS, one emerging strategy is to target the glial cells which contribute to the progression phase of disease, with the ultimate goal to slow disease progression. The aim of our studies was to investigate how glial cells such as astrocytes contribute to motor neuron death and develop therapies to inhibit this glial toxicity. We hypothesized that co-culturing ALS astrocytes in vitro with motor neurons would result in motor neuron death. Using both astrocytes isolated from the mouse model of ALS as well as from post-mortem ALS spinal cord, we show these astrocytes are toxic to motor neurons in vitro. Our data represents the first report to show a common pathway to motor neuron death mediated by astrocyte dysfunction between familial ALS and the more common sporadic form of ALS. To investigate mechanisms involved in this astrocyte-mediated motor neuron death, we examined whether inflammatory pathways were activated in the astrocytes. We found significant activation of the NF-kB pathway in ALS astrocytes so we designed a gene therapy vector to inhibit this activation. Preliminary data suggests that inhibiting the NF-kB pathway in astrocytes can reduce inflammatory gene expression and may increase survival in the ALS mouse model. Future studies will involve more rigorous testing of this gene therapy in the ALS mouse model as well as in our co-culture model of sporadic ALS.</p> 2010-07-29 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1270479273 http://rave.ohiolink.edu/etdc/view?acc_num=osu1270479273 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biomedical Research |
| spellingShingle |
Biomedical Research Haidet, Amanda M. Gene Therapy for Neuromuscular Disorders |
| author |
Haidet, Amanda M. |
| author_facet |
Haidet, Amanda M. |
| author_sort |
Haidet, Amanda M. |
| title |
Gene Therapy for Neuromuscular Disorders |
| title_short |
Gene Therapy for Neuromuscular Disorders |
| title_full |
Gene Therapy for Neuromuscular Disorders |
| title_fullStr |
Gene Therapy for Neuromuscular Disorders |
| title_full_unstemmed |
Gene Therapy for Neuromuscular Disorders |
| title_sort |
gene therapy for neuromuscular disorders |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2010 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1270479273 |
| work_keys_str_mv |
AT haidetamandam genetherapyforneuromusculardisorders |
| _version_ |
1719428881295867904 |