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.

Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment

“…However, gene therapy approaches have shown significant potential. For example, Gray and colleagues used engineered adeno-associated virus (AAV) vectors to restore WT gigaxonin expression in GAN -/mice and achieved persistent transgene expression in the central and peripheral nervous systems for more than 1 year, accompanied by reduced neuronal IF protein aggregation (76). More recently, the Gray laboratory conducted clinical trials of intrathecal delivery of a scAAV9/JeT-GAN vector to reexpress WT gigaxonin in GAN patients (NCT02362438).…”

The special considerations of gene therapy for mitochondrial diseases

“…Mitochondrial disorders often affect multiple organ systems and global expression of the transgene will be required Previous gene therapy trials have largely focused on the treatment of conditions affecting specific tissues, such as optic 1 or neurological disorders, 2,35,36 which only require transgene delivery to very specific locations. Unfortunately, most mitochondrial disorders affect multiple organ systems, and will thus require the rescue vector to be expressed throughout the body in order to produce any significant improvement in the patient's condition.…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…AAVs are capable of infecting cells that are not going through mitosis and persist primarily as non-integrative episomal units. Therefore, various AAV serotypes have been developed with particular tropism for cells and tissues of interest, including neurons and glia, and tested in pre-clinical mouse models of LSDs (Bailey et al, 2018). AAV-mediated GT successfully improved the phenotypes of GM1 gangliosidosis, MPS I & IIIB, Sandhoff disease, metachromatic leukodystrophy, and Krabbe disease (Gonzalez and Baldo, 2017).…”