@article{4b67e25937574a2caae12d0c27935465,
title = "Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy",
abstract = "An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs). The pathologic signature of GAN is giant axonal swellings filled with disorganized accumulations of IFs. Herein, we describe the development and characterization of the AAV vector carrying a normal copy of the human GAN transgene (AAV9/JeT-GAN) currently employed in the clinical trial. Treatment with AAV/JeT-GAN restored the normal configuration of IFs in patient fibroblasts within days in cell culture and by 4 weeks in GAN KO mice. IT delivery of AAV9/JeT-GAN in aged GAN KO mice preserved sciatic nerve ultrastructure, reduced neuronal IF accumulations and attenuated rotarod dysfunction. This strategy conferred sustained wild-type gigaxonin expression across the PNS and CNS for at least 1 year in mice. These results support the clinical evaluation of AAV9/JeT-GAN for potential therapeutic outcomes and treatment for GAN patients.",
keywords = "AAV9, adeno-associated virus, biodistribution, dorsal root ganglia, fibroblast, gene therapy, giant axonal neuropathy, gigaxonin, intrathecal, sciatic nerve",
author = "Bailey, {Rachel M.} and Diane Armao and {Nagabhushan Kalburgi}, Sahana and Gray, {Steven J.}",
note = "Funding Information: This study was supported by Hannah's Hope Fund, the NIH National Institute of Neurological Disorders and Stroke (NS087175, S.J.G.; NS095515, R.M.B.), and the NIH National Institute of Child Health and Human Development (HD040127, R.M.B.; U54HD079124, the Mouse Behavioral Phenotyping Laboratory of the UNC IDDRC). Indirect administrative support for S.J.G. was provided by the Research to Prevent Blindness to the UNC-CH Department of Ophthalmology. The UNC-CH Translational Pathology Laboratory (TPL) and the LCCC Animal Studies Core are supported, in part, by an NCI Center Core Support Grant (CA16086) to the UNC Lineberger Comprehensive Cancer Center. We thank L. Bachaboina, J.C. Fox, and M. Keener for technical support with animal care, necropsies, histology, and early vector assessments and V. Zaric for technical support with qPCR and qRT-PCR analyses. We acknowledge K. Burns at UNC-CH, the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine at UNC-CH, and the Mouse Behavioral Phenotyping Laboratory of the UNC IDDRC. We thank B. Midkiff in the UNC-CH TPL for technical assistance. Intracranial injections were performed within the UNC-CH LCCC Animal Studies Core Facility. We thank Dr. Y. Yang (Stanford University, USA) for providing the GAN/Y mice and Dr. J.P. Julien (Universite Laval, Canada) for providing the GAN/J mice. We thank Dr. J. Samulski for insightful discussions and the use of UNC Gene Therapy Center resources/equipment, as well as the UNC-CH Vector Core facility for the production of some vectors used in these studies. Finally, we thank Dr. C. B{\"o}nnemann and his team at NIH/NINDS for their collaboration and the initiation of the phase 1 GAN clinical trial. Funding Information: This study was supported by Hannah{\textquoteright}s Hope Fund , the NIH National Institute of Neurological Disorders and Stroke ( NS087175 , S.J.G.; NS095515 , R.M.B.), and the NIH National Institute of Child Health and Human Development ( HD040127 , R.M.B.; U54HD079124 , the Mouse Behavioral Phenotyping Laboratory of the UNC IDDRC). Indirect administrative support for S.J.G. was provided by the Research to Prevent Blindness to the UNC-CH Department of Ophthalmology. The UNC-CH Translational Pathology Laboratory (TPL) and the LCCC Animal Studies Core are supported, in part, by an NCI Center Core Support Grant ( CA16086 ) to the UNC Lineberger Comprehensive Cancer Center. We thank L. Bachaboina, J.C. Fox, and M. Keener for technical support with animal care, necropsies, histology, and early vector assessments and V. Zaric for technical support with qPCR and qRT-PCR analyses. We acknowledge K. Burns at UNC-CH, the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine at UNC-CH, and the Mouse Behavioral Phenotyping Laboratory of the UNC IDDRC. We thank B. Midkiff in the UNC-CH TPL for technical assistance. Intracranial injections were performed within the UNC-CH LCCC Animal Studies Core Facility. We thank Dr. Y. Yang (Stanford University, USA) for providing the GAN/Y mice and Dr. J.P. Julien (Universite Laval, Canada) for providing the GAN/J mice. We thank Dr. J. Samulski for insightful discussions and the use of UNC Gene Therapy Center resources/equipment, as well as the UNC-CH Vector Core facility for the production of some vectors used in these studies. Finally, we thank Dr. C. B{\"o}nnemann and his team at NIH/NINDS for their collaboration and the initiation of the phase 1 GAN clinical trial. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jun,
day = "15",
doi = "10.1016/j.omtm.2018.02.005",
language = "English (US)",
volume = "9",
pages = "160--171",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Nature Publishing Group",
}