Amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases worldwide. It is a devastating motor neuron (MN) disease, resulting in muscle paralysis and ultimately respiratory failure leading to death. There is currently no effective therapy to significantly alter the disease course in humans. 90% of ALS cases are sporadic (SALS), in which no known genetic or environmental cause is known. The remaining 10% of patients have a familial variant of the disease (FALS). Approximately 20% of FALS have mutations within the gene encoding superoxide dismutase 1 (SOD1). For these FALS patients, mutant SOD1 (mtSOD1) is a clear pharmacological target, and it is well established that reduction of mtSOD1 prolongs lifespan in several ALS mouse models. The clinical and pathological presentation of both FALS and SALS is identical, in which striking gliosis, increase proliferation of astrocytes and microglia, occurs accompanied by selective MN cell death. Recent studies using mtSOD1 animal models have shown that non-neuronal cells contribute to disease onset and progression, and evidence for non-cell autonomous motor neuron death has mounted. Indeed, it has been shown that the reduction of mtSOD1 expression in astrocytes by breeding transgenic mice contacting the floxed mtSOD1 with mice expressing Cre from the glial fibrillary acidic protein (GFAP) promoter had significant effects in the disease These crosses showed that disease progression was significantly slowed and the effect on survival was profound. However, an important question remains from these studies: What is the timing for removing mtSOD1 from astrocytes that delays disease progression and extends survival? We believe that it is important to identify the latest time point during disease progression in which the removal of mtSOD1 is still efficacious, as many patients are diagnosed after disease onset. Therefore, it is crucial for therapy development to identify the 'point of no return'in ALS. We recently reported a very efficient method to target glia, predominantly astrocytes, in the adult Central Nervous System via systemic delivery of a vector based on Adeno-associated virus serotype 9 (AAV9).This discovery will enable our laboratory to efficiently suppress mtSOD1 in glia at various time points during disease (onset, early and late phase) in ALS mouse models allowing us to address this important question and forming the basis of this translational proposal. Specifically, we will: Determine the clinically relevant time frames when reduction of mtSOD1 in astrocytes provides therapeutic benefit. At the completion of this project, it is our expectation that we will have identified the optimal as well as the latest time points for decreasing mtSOD1 in glia that results in delayed disease progression and extends survival of SOD1G93A mice. This work will generate important insights to unravel the optimal therapeutic time window for attenuating aberrant glial cell toxicity in ALS providing the basis for a translational approach to remove mtSOD1 in patients.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease, which results in muscle paralysis and ultimate respiratory failure and death. The underlying cause for ALS remains unknown with no cure, yet a target for familial ALS exists, in which patients have mutations within the gene encoding for superoxide dismutase 1 (SOD1). Targeted deletion of mutant SOD1 in astrocytes has led to substantial increase in lifespan in rodent models of this disease. In this proposal, we will investigate the timing to reduce mutant SOD1 in astrocytes using a novel gene delivery approach that we have discovered to efficiently target astrocytes. This proposal will help to define clinically meaningfu time points to intervene in aberrant glial toxicity in ALS. If successful, we believe this delivery approach will be translatable to human ALS patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Gubitz, Amelie
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Nationwide Children's Hospital
United States
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Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi et al. (2013) Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther 21:2148-59