A gene therapy approach involving transfer of the GAN gene into nerve cells is presently being investigated as a potential option for addressing a rare neurodegenerative condition in children. Biallelic variants of GAN resulting in the loss of function of the encoded protein, gigaxonin, cause giant axonal neuropathy. This severe disorder manifests in early childhood and is characterized by progressing motor and sensory peripheral neuropathy, central nervous system involvement and characteristic tightly curled hair. Most affected children will need to use a wheelchair in their second decade of life and die in their thirties. Gigaxonin, a Cul3 ubiquitin ligase adaptor, is involved in the regulation of protein degradation within cells. By facilitating degradation of neurofilaments it contributes to maintaining proper neuronal structure and function.

Results of an ongoing clinical phase 1 study of the gene therapy scAAV9/JeT-GAN have been published in The New England Journal of Medicine. This approach uses a vector based on adeno-associated virus (AAV) to deliver a functional version of the GAN gene along with a synthetic promoter into neuronal cells to initiate gene expression and production and release of the gigaxonin protein. In the study, 14 affected children received a single intrathecal injection of scAAV9/JeT-GAN. Four different dosages were applied. Over a year, there are indications of a possible clinical benefit in terms of a positive change in the decline of motor function. Further studies are needed to evaluate the safety and efficacy of this potential gene therapy to treat patients with giant axonal neuropathy