Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy
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 t...
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doaj-dca15162736945cda152a854ea3b7a7e2020-11-25T01:49:23ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012018-06-019160171Development of Intrathecal AAV9 Gene Therapy for Giant Axonal NeuropathyRachel M. Bailey0Diane Armao1Sahana Nagabhushan Kalburgi2Steven J. Gray3Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author: Steven J. Gray, UT Southwestern Medical Center, NA2.508, 6000 Harry Hines Blvd., Dallas, TX 75390-8593, USA.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: gene therapy, adeno-associated virus, giant axonal neuropathy, AAV9, intrathecal, fibroblast, dorsal root ganglia, sciatic nerve, gigaxonin, biodistributionhttp://www.sciencedirect.com/science/article/pii/S2329050118300172 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rachel M. Bailey Diane Armao Sahana Nagabhushan Kalburgi Steven J. Gray |
spellingShingle |
Rachel M. Bailey Diane Armao Sahana Nagabhushan Kalburgi Steven J. Gray Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy Molecular Therapy: Methods & Clinical Development |
author_facet |
Rachel M. Bailey Diane Armao Sahana Nagabhushan Kalburgi Steven J. Gray |
author_sort |
Rachel M. Bailey |
title |
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy |
title_short |
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy |
title_full |
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy |
title_fullStr |
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy |
title_full_unstemmed |
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy |
title_sort |
development of intrathecal aav9 gene therapy for giant axonal neuropathy |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2018-06-01 |
description |
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: gene therapy, adeno-associated virus, giant axonal neuropathy, AAV9, intrathecal, fibroblast, dorsal root ganglia, sciatic nerve, gigaxonin, biodistribution |
url |
http://www.sciencedirect.com/science/article/pii/S2329050118300172 |
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