Giant Axonal Neuropathy (GAN, OMIM #256850) is a rare chronic neurodegenerative disease characterized by enlarged axons with disordered microtubules and intermediate filaments (IFs), which is fatal by the third decade of life. The disease pathology is due to homozygous loss-of- function mutations in the GAN gene, which encodes the protein gigaxonin. The underlying pathology is due to the disorganization and accumulation of IFs, including vimentin, alpha- internexin, neurofilaments, peripherin, and GFAP. GAN patients have normal cognitive function, and the most severe (and fatal) symptoms of GAN are the result of dysfunction and death of motor and sensory neurons in the spinal cord and DRG. The phenotypic contribution of IF dysfunction in other tissues such as the brain, autonomic nerves, and peripheral organs is poorly understood. Since 2008 we have been developing a gene transfer approach to treat GAN using intrathecal delivery of AAV9/GAN vectors, funded entirely by a small non-profit foundation called Hannah's Hope Fund. This effort culminated in a preIND (investigational new drug) meeting with the FDA in January 2012, and a RAC meeting for a proposed clinical trial in June 2013. Submission of an IND for a Phase I safety GAN gene therapy clinical trial is expected in summer of 2013, focused on rescuing spinal cord motor and sensory neurons. Sponsored by Hannah's Hope Fund, this trial will occur at the NIH Clinical Center under the direction of Dr. Carsten Bonnemann. This Phase I trial is aimed at establishing the safety of our general gigaxonin gene transfer approach in older patients that are eager to participate and otherwise untreatable. This patient population is made up of individuals that will be dead or too far progressed in their disease to participate in a late trial. While the Phase I trial is underway, this proposal aims to better characterize GAN in ways that could inform a Phase II/III trial and also identify new therapeutic targets if our approach needs to be modified. Further, it aims to optimize the gene transfer approach and develop a GAN knock-out rat.

Public Health Relevance

This project aims to develop and test approaches to use gene therapy to treat a rare and fatal pediatric neurodegenerative disease called Giant Axonal Neuropathy (GAN). These preclinical studies will aid in the selection of outcome measures in a proposed human clinical trial for GAN. If successful, these studies will have broader therapeutic implications for a wide range of inherited neurological disorders including spinal muscular atrophy, amyotrophic lateral sclerosis, and Friedrich's Ataxia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS087175-03
Application #
9039495
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Nuckolls, Glen H
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Ramsingh, Arlene I; Gray, Steven J; Reilly, Andrew et al. (2018) Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLoS One 13:e0198154
Armao, Diane; Bailey, Rachel M; Bouldin, Thomas W et al. (2016) Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease. Clin Auton Res 26:307-13
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