Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease in humans and there is currently no cure. Although rodent ALS models have provided vital information on disease mechanisms, they have failed to predict therapeutic responses in affected patients resulting in no significant impact on outcomes despite millions of dollars spent on clinical trials. This marked translational inefficiency underscores the need for robust models that more closely recapitulate human ALS. Canine degenerative myelopathy (DM) is an inherited, progressive adult-onset neurodegenerative disease with clinical, histopathologic and genetic parallels to human ALS. We identified an E40K missense mutation in SOD1 resulting in SOD1 aggregate accumulations within cells, the putative mechanism of disease in dogs with DM and in both familial and sporadic forms of human ALS. We have formed a new multi-institutional CTSA-linked collaborative enterprise that includes board-certified veterinary neurologists with expertise in canine DM, a community of ALS researchers, and industry entities with the shared long-term goal of conducting comparative veterinary clinical trials in canine neurologic diseases as a mechanism to inform and enhance translational medicine. As such, the overarching purpose of this proposal is to develop an innovative neurotranslational platform trial framework for use in dogs with DM and to use this to evaluate novel therapies. This will be accomplish by first establishing a collaborative platform to conduct clinical trials in canine DM and then using this mechanism to test the therapeutic efficacy of intrathecal (IT) administration of AAV gene therapy to silence SOD1 production in affected dogs. Specifically, we will create a permanent infrastructure to administer a perpetual platform trial and develop a universal DM ?patient? registry that will capture and archive longitudinal veterinary patient data and standardize trial enrollment, randomization and reporting. Members of the network will develop consistent procedures for patient assessment, establish clear parameter regarding outcome measures, explore emerging biomarkers to enhance go/no-go decision-making and bank biospecimens to enhance performance of future studies related to DM. Once this has been accomplished, the infrastructure will be used to conduct a multicenter clinical ?test trial? to compare the effects of a novel AAV.iSOD1 treatment on disease progression and alterations of biomarkers shared between canine DM and human ALS. Ultimately, the establishment of this innovative platform trial design in DM will support an on-going effort through which state-of the-art therapeutic strategies can be evaluated for safety and efficacy not just in ALS, but also in dogs with a variety of other naturally occurring neurologic diseases before entering the human clinical arena.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease in people. Despite best efforts, nearly all trials of new therapies have failed to improve outcomes. This project will leverage spontaneous degenerative myelopathy (DM) in dogs, a relevant model of human ALS, to interrogate and optimize a novel therapeutic approach, with the ultimate goal of markedly improving translational efficiency.