Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons resulting in stiffness, slowing of movement, and severe muscle wasting and weakness. Patients die in 3-5 years secondary to failure of respiratory muscles. There are no effective therapies for ALS. The discovery of superoxide dismutase (SOD1) mutations as causative for a proportion of the inherited forms of ALS led to the generation of rodent SOD1 mutation models in the hope that these animal models would provide new therapeutics. Although the rodent ALS models have provided many advantages for the study ALS and therapeutics, such animal models have failed to accurately predict therapeutic responses in ALS patients. However, clinical similarities between the inherited SOD1-related ALS and the more prevalent ALS with no SOD1 mutation, and recent findings of SOD1 aggregates in tissues of sporadic ALS patients, suggest that further study of SOD1 still is relevant to all ALS. Canine degenerative myelopathy (DM) is an inherited, progressive adult-onset neurodegenerative disease that has many similarities to human ALS and potentially serves as an important novel model for therapy development. Recently, we found that an E40K missense mutation in SOD1 underlies most cases of canine DM. Similarities between the canine and human nervous systems and homogeneity of the DM phenotype will facilitate translation of therapies into ALS patients. A promising therapeutic strategy using antisense oligonucleotides (ASOs) that target SOD1 mRNA to suppress SOD1 protein was recently demonstrated in a rodent ALS model. The SOD1 ASO decreased amounts of SOD1 in neurons and slowed disease progression. Studies of canine DM, with its spontaneous SOD1 mutation, may yield data more relevant to human ALS and help advance SOD1 ASO clinical trials in ALS patients. Guided by supportive preliminary data, studies will be conducted to achieve the following Specific Aims: 1) Evaluate the safety and pharmacokinetics of intrathecal delivery of a SOD1 ASO in normal dogs to develop an optimized protocol for therapy in DM. Acquisition of such data in normal dogs is critical for the development of this novel treatment approach before instituting a pilot study in privately owned DM-affected dogs. A study of ASO therapy in canine DM as a disease model for ALS is significant, because it should facilitate the translation of a therapeutic approach from laboratory to clinic. 2) Evaluate the safety and preliminary therapeutic effects of intrathecally administered SOD1 ASO in DM-affected dogs. If canine DM is to serve as an effective disease model by which to evaluate ALS therapies, we must demonstrate therapeutic efficacy through a comparative approach using objective measures of disease progression that are shared across species. MUNE is expected to serve as an ideal biomarker for therapeutic translation in DM-affected dogs because the technique is also performed in ALS patients. The proposed research is innovative because it focuses on a promising therapeutic approach in a naturally-occurring canine disease that is analogous to human ALS.

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Canine degenerative myelopathy (DM) is an inherited adult-onset neurodegenerative disease of dogs caused by a mutation in the SOD1 gene and thus is similar to amyotrophic lateral sclerosis (ALS). We propose that this larger animal disease model will be beneficial in the preclinical development of drug therapies and more accurately predict therapies that will halt or slow progression of ALS.

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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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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