Adeno-associated Viral Vector Modification for Targeted Motor Neuron Therapy

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DESCRIPTION (provided by applicant): Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA), are progressive neurodegenerative disorders that share the common characteristic of upper and/or lower motor neuron (MN) degeneration. Although the molecular mechanisms underlying MND are not entirely clear, all forms ultimately lead to apoptotic motor neuron death. Therapeutic strategies for MND, using trophic factors, or anti-apoptotic proteins can confer MN protection regardless of the specific mechanism of injury. Currently, gene therapy is one of the most promising candidates to deliver these treatments in MND, using lentiviral and adeno-associated viral (AAV) vectors. Because of the attractive safety profile of AAV vectors a variety of clinical trials are ongoing or planned for application to neurodegenerative diseases including ALS. Despite their appealing characteristics, AAV vectors have high affinity for skeletal muscle, as well as limited tropism for axon terminals, impeding MN gene delivery after IM injection. These limitations halted the aggressive development of a clinical trial for the treatment of ALS through intramuscular AAV.IGF-I injection. To overcome this barrier, we have modified the vector's capsid through the insertion of a novel peptide (Tet1) with high MN affinity and retrograde transport, increasing AAV mediated MN gene delivery. The present grant seeks support to identify the optimal targeted AAV vector for enhanced MN gene delivery, and demonstrate improved survival in the rat model of ALS compared to the earlier generation vector. Substantially improved retrograde delivery will prompt a return to the aggressive development of a clinical trial for ALS gene therapy. Our application will attempt to demonstrate that: 1. Capsid Mutation of the AAV Cap gene, incorporating novel neuronal binding peptides into the virus' coat, can increase the efficiency and specificity of MN gene delivery. 2. Targeted AAV-mediated IGF-I gene expression will protect MNs in SOD1 rats. 3. Peptide insertion may enhance neuronal delivery following alternative delivery routes, such as intra-arterial and intrathecal injections. PUBLIC HEALTH RELEVANCE: Death and disability in Motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS), result from death of cells in the nervous system called motor neurons (MN). In the present application, we will engineer viruses for safe and enhanced delivery of therapeutic genes to motor neurons. These viruses will be capable of delivering genes to the spinal cord after simple muscle injection, providing a safe approach to gene therapy for ALS.