Interrogation of Neurological Pathologies Associated with Mutations in Kif1a

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PROJECT SUMMARY KAND (KIF1A-associated neurological disorder) is caused by mutations in the KIF1A gene - a microtubule- dependent motor protein that is responsible to transport cellular cargos in neurons. The majority of mutations are dominant missense mutations that cluster in the conserved motor domain of the protein and lead to a spectrum of neurological phenotypes beginning in childhood, including muscle weakness, microcephaly, peripheral neuropathy, intellectual disability, autism, optic nerve and cerebellar atrophy. Without treatment, children and adults affected by KAND suffer from the progressive loss of their mobility, vision and even early death due to intractable epilepsy and complications of respiratory illness. Mouse models are a critical component to both understanding disease mechanisms and to serve as a key platform for preclinical testing of novel therapeutics. Unfortunately, mouse models to advance our understanding of KAND biology and therapeutics are severely lacking, although very much in reach. This proposal aims to build on our current knowledge of KAND to design mouse models that will not only provide patient avatars for KAND disease pathophysiology but will also serve to address important questions around the timing of therapeutic rescue, effects of overexpression, what cell types are required for effective treatment and how much genetic correction is required for disease modulation. Importantly, the models will be valuable for pre- clinical testing of therapeutics. The work described in this proposal leverages recently published Natural History Studies by our clinical collaborator, Dr. Wendy Chung, which provides ongoing insight into the clinical features, prevalence and biomarkers associated with this patient community. Our overall goals are to provide the scientific community with well designed, rigorously tested mouse models that recapitulate key aspects of KAND disease manifestations to be used, without restriction, throughout academia and industry for research and therapeutic discovery.