Giant Axonal Neuropathy (GAN)

National Center For Advancing Translational Sciences

Investigators

Abstract

Assay Development & Screening Technology group (ADST) is designed to advance therapeutic development through research and development of innovative assay (test designs) and chemical library screenings. Giant Axonal Neuropathy (GAN) is a rare, autosomal recessive neurological disorder affecting the neurofilament architecture that defines the shape and size of neurons vital to normal nerve physiology. This genetic disease displays an early-onset phenotype and manifests as a progressive decline in neurological function leading to death. Mutations in the GAN gene, encoding the gigaxonin protein, a substrate adaptor of an E3 ubiquitin ligase, form the basis of disease pathophysiology. It is currently thought that the neuronal degeneration is due to the failure of cells to properly degrade intermediate filaments through the ubiquitin proteasome. The goals of the Hannas Hope Fund are to identify promising treatments that restore or functionally compensate for mutant gigaxon in patients with GAN. With financial support from the Hannas Hope Fund we are focused on (1) development of HTS coordinated cell-based reporter assays in a gigaxonin deficient background to permit screening of chemical libraries that reverse/attenuate intermediate filament aggregation. (2) Conducting quantitative high throughput screening (qHTS) of libraries of drug and bioactive compounds. (3) Perform a gene silencing screen to identify in combination with compound screening genes capable of modifying the GAN -/- cellular phenotype. (4) Develop follow-up assays for the validation and characterization of phenotype-modifying compounds and genes.