Talk abstracts

Talk on Wednesday 03:00-03:15pm submitted by Shibi Likhite

AAV9-mediated Suppression of SOD1 as a Potential Therapy for Amyotrophic Lateral Sclerosis

Shibi B Likhite (Molecular, Cellular & Developmental Biology, The Ohio State University), Kevin D Foust (Neuroscience, The Ohio State University), Laura Ferraiuolo (Center for Gene Therapy, Research Institute at Nationwide Childrens Hospital), Leah Schmelzer (Center for Gene Therapy, Research Institute at Nationwide Childrens Hospital), Lyndsey Braun (Center for Gene Therapy, Research Institute at Nationwide Childrens Hospital)

Abstract:
Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurodegenerative disease, characterized by progressive and fatal loss of motor neurons. Mutations in the Superoxide dismutase 1 (SOD1) gene are one of the leading causes of familial ALS while misfolded wild-type SOD1 is suggested to be involved in the pathogenesis of sporadic ALS. Here, we determined the feasibility and efficacy of post-natal downregulation of SOD1 as a therapeutic strategy in ALS, using a novel approach of Adeno Associated Virus Serotype 9 (AAV9)-mediated shRNA delivery. SOD1G93A mice, overexpressing human mutant SOD1, were injected intravenously at post-natal day 1 (P1), P21 or P85 with AAV9-SOD1 shRNA. P1-treated mice showed persistent transduction of AAV9-SOD1 shRNA in motor neurons and astrocytes while P21 and P85 treated mice showed predominant astrocytic transduction. Injected mice showed reduced levels of mutant SOD1 in the spinal cord. Both P1 and P21 injected mice showed improved performance on behavioral tasks. P1 injected mice showed significant delay in the disease onset and progression while P21 and P85 injected mice had a significant delay in disease progression. Importantly, all treatments significantly extended the median survival of SOD1G93A mice by 30-50 days. Injection of AAV9-SOD1 shRNA, even after the disease onset, in slow progressing SOD1G37R mice resulted in 84 days extension in the median survival. Further, AAV9-SOD1 shRNA administration in wild-type mice revealed no adverse effects. Finally, intrathecal administration of AAV9-SOD1 shRNA in non-human primates (Cynomolgus monkeys) resulted in efficient spinal cord transduction and significant SOD1 reduction. Thus, the success of post-natal suppression of SOD1 toxicity in ALS mice, long-term safety assessment in wild-type mice and robust SOD1 knockdown in non-human primates sets the stage for future clinical trials. Moreover, the involvement of SOD1 in familial and sporadic ALS underlines the potential of this approach as a gene therapy for ALS.

References:
Boillee, S., Vande Velde, C. & Cleveland, D.W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39-59 (2006).
Boillee, S., et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392 (2006).
Yamanaka, K., et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11, 251-253 (2008).
Bosco, DA., et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13: 1396–1403 (2010).
Haidet-Phillips, AM., et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29, 824–828 (2011).
Foust, K.D., et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27, 59-65 (2009).

Keywords: Amyotrophic Lateral Sclerosis (ALS), Adeno Associated Virus Serotype 9 (AAV9), Superoxide Dismutase 1 (SOD1)