Treatment of Peripheral Nervous System Dysfunction in Giant Axonal Neuropathy

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 DESCRIPTION (provided by applicant): Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disorder that affects both the central and peripheral nervous systems (CNS and PNS). Around 3 years of age, patients present with a progressive peripheral neuropathy that affects sensory, motor, enteric and autonomic nerve function. GAN is ultimately fatal by the third decade of life as no treatment currently exists. GAN is caused by autosomal recessive loss-of- function mutations in the GAN gene, which encodes for the gigaxonin protein that plays a role in the organization/degradation of intermediate filaments (IFs). A pathological hallmark of GAN is large axonal swellings filled with disorganized aggregates of IFs that are apparent throughout the nervous system and other organ systems. Preclinical studies by our group show that GAN gene replacement therapy in GAN patient fibroblasts and GAN knock-out (KO) mice results in the clearance of IF aggregates. An NIH-sponsored Phase I study is underway to test the safety of Intrathecal (IT) delivery of scAAV9/JeT-GAN to treat the most severe aspects of GAN, namely the motor and sensory neuropathy. It is currently unknown, however, if IT delivery of scAAV9/Jet-GAN will treat additional peripheral targets, such as the autonomic nervous system. The overall objectives of this proposal are to identify gene replacement therapies for specific components of the PNS, such as autonomic, enteric and somatosensory nervous tissues. Experiments under Aim 1 will characterize novel pathological and behavioral phenotypes of GAN KO mice and rats and mutant GAN knock-in rats. For the first time, our preliminary data shows IF aggregate in the autonomic nervous tissues of GAN KO mice, which may mimic salient aspects of the human disease. Under Aim 2 we will test naturally occurring and engineered viral capsids for targeting of the autonomic, enteric and somatosensory systems of rodents. Experiments under Aim 3 will test the efficacy of the therapies identified in Aim 2 to treat the PNS-specific disease markers identified in Aim 1 in GAN rodent models. Results from these studies will be immediately applicable to the ongoing Phase 1 clinical trial for GAN and will aid in the development of gene therapy for additional disorders involving peripheral and autonomic dysfunction.