NEW THERAPEUTIC APPROACHES AND THEIR READOUT: O.19First-in-human intrathecal gene transfer study for giant axonal neuropathy: review of safety, immunologic responses and interim analysis of efficacy

Abstract

Giant axonal neuropathy (GAN) is a rare childhood onset neurodegenerative disorder of the peripheral and central nervous system. Recessive GAN mutations cause loss of function of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure. We report on a single site, phase I, non-randomized, open label dose escalation gene transfer study for GAN (NCT02362438), a first-in-human intrathecal (IT) AAV9 mediated gene transfer trial for any indication. 9 GAN patients have been dosed at three dose levels (ranging from 3.5 × 1013vg to 1.8 × 1014vg) with scAAV9-JeT-GAN, with up to 2 year post-gene transfer follow up. We review safety and immunologic response to the gene vector and transgene (serum and CSF AAV9 neutralizing antibody titers, interferon-γ ELISpot analysis to GAN and AAV9 epitopes, CSF and peripheral cytokine analysis and white blood cell flow cytometry), and present an interim efficacy analysis. GAN natural history study data is used for comparison of outcome measures which include: Motor function measure 32 (MFM32), Neuropathy impairment score (NIS), Friedreich's Ataxia rating scale (FARS), myometry, grip and pinch strength, timed testing, electrophysiology, and neuroimaging. We highlight the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer. The efficacy interim analysis highlights several key aspects: Feasibility for adequately targeting the nervous system, preferred IT dosing regimens needed for effective transduction, relevance of baseline neurologic impairment and disease progression in patient selection and stratification. This data also provides insight into the immunological implications of gene transfer with concomitant immunosuppressive regimens and their impact on AAV9 gene transfer safety and efficacy. This study is a proof of concept for IT gene transfer as a strategy for gene replacement targeting the central nervous system.