Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy

Rachel M. Bailey, Diane Armao, Sahana Nagabhushan Kalburgi, Steven J. Gray

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 ( 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.

Original languageEnglish (US)
Pages (from-to)160-171
Number of pages12
JournalMolecular Therapy - Methods and Clinical Development
StatePublished - Jun 15 2018


  • AAV9
  • adeno-associated virus
  • biodistribution
  • dorsal root ganglia
  • fibroblast
  • gene therapy
  • giant axonal neuropathy
  • gigaxonin
  • intrathecal
  • sciatic nerve

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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