Background: GAN is a rare pediatric neurodegenerative hereditary neuropathy affecting the central and peripheral nervous system. Recessive GAN mutations cause dysfunction of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure with death by the 2nd to 3rd decade of life.
Objectives: We are conducting a first-in-human intrathecal (IT) AAV9 mediated gene transfer trial for GAN (NCT02362438). This is a single site, phase I, non-randomized, open label dose escalation study. Twelve subjects have been dosed at four dose levels (ranging from 3.5×1013 vg to 3.5×1014 vg) with scAAV9-JeT-GAN, with follow up data as far as 36 months post gene transfer.
Results: We present here a review of safety data in the study, as well as interim study analysis data evaluating efficacy in this study. We utilize longitudinal natural history study data for GAN for comparison of outcome measures post gene transfer applying a Bayesian method of statistical analysis. Outcome measures of interest include: motor function measure 32 (MFM32), neuropathy impairment score (NIS), Friedreich Ataxia Rating Scale (FARS), myometry, and electrophysiologic data.
Conclusions: This work highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer. We further review efficacy in this study to highlight several key aspects: 1) feasibility for targeting the nervous system, 2) IT dosing regimens needed for effective transduction, 3) relevance of baseline neurologic impairment and disease progression in patient selection and stratification. We review statistical methodology used to evaluate efficacy in an ultrarare disease with a natural history comparator. We further review here novel and systematically reviewed immunologic analysis including: 1) Analysis of B and T cell based responses following an IT gene transfer; 2) Effect of baseline AAV9 seropositive status, 3) Feasibility of inclusion of biallelic null mutation patients with targeted T cell immune modulation. This study highlights key considerations in the field of gene therapy including: feasible doses to target the nervous system; inclusion of biallelic null subjects for gene transfer, the role of immune modulation in gene transfer approaches, and statistical method considerations for ultra-rare disease populations.