Gene therapy using Adeno-associated viral vectors (AAVs) is a very promising tool for treatment of many mus- culoskeletal disorders. Multiple strategies are currently in clinical trials using either intramuscular (IM) or intra- vascular (IV) delivery of the vector. Despite promising initial results, the effect is only local for IM treatment or requires a large amount of virus for IV delivery since the dose is calculated per kilogram body weight. While suitable for small children, AAV therapies become more problematic for the treatment of teenagers or adults due to high vector production costs as well as potential safety concerns at very high doses. In addition, many muscular disorders also display pathology of the nervous system (NS). Therefore, efficient simultaneous tar- geting of both the muscle and NS would likely enhance therapeutic outcomes. In this project, our objective is to test the efficiency of delivering the gene therapy vectors through cerebral spinal fluid (CSF) instead of IV injec- tions in order to target both muscle and nervous system. This delivery technique is innovative and based on our preliminary data, which supports our hypothesis that CSF delivery of the vector could substantially reduce the required amount of viral vector in order to target both muscle and NS as higher viral vector amount is re- quired for transducting both NS and muscles using IV.
In Aim 1, we will determine optimal CSF dosing in wild type mice. We will also test CSF dosing in a mouse model of Duchenne Muscular Dystrophy (the Dup2 mouse model) to ensure that muscle damage does not alter vector spreading.
In Aim 2, we will use the Dup2 mouse model to assess the extent to which CSF delivery of a therapeutic vector (AAV9.ACCA) can achieve therapeu- tic effects. The experiments proposed in Aim 3 will compare the ability of IV and CSF delivery routes to target muscles and NS in non-human primates when using a tenfold lower dose compared to previous studies using IV delivery. This collaborative project will be achieved thanks to the combined expertise of the several laborato- ries: Dr. Wein who has generated both the AAV9.ACCA vector and the Dup2 mouse model used in this study; Dr. Flanigan, an expert in gene therapy and neuromuscular disorders, and Drs. Burghes, Arnold and Meyer, world-renown and highly successful leaders in gene therapy and CSF delivery techniques. The impact of this study cannot be overstated, as the results would be of high interest globally for a very large patient community, as well as researchers working on other neuromuscular disorders. The results from this study could be applied to many neuromuscular disorders.

Public Health Relevance

Gene therapy using adeno-associated virus (AAV) is a promising tool for the treatment of neuromuscular disorders. This proposal is relevant to public health as it seeks to improve the efficacy of AAV treatment for simultaneous targeting the central nervous system and muscle for a variety of neuromuscular disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
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Carifi, Emily Foran
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Nationwide Children's Hospital
United States
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