O.10 First-in-human intrathecal gene transfer study for giant axonal neuropathy: Preliminary review of long-term efficacy and safety

Abstract

Giant axonal neuropathy (GAN) is a rare and fatal pediatric neurodegenerative disorder affecting the central and peripheral nervous system. Recessive variants in the <i>GAN</i> gene cause dysfunction of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure with death by the second to third decade of life. We are conducting a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438). This is an ongoing single site, phase I, non-randomized, open label dose escalation trial with lead-in and GAN natural history data serving for comparison. Fourteen GAN participants ages 6 years to 14 years old have received a single IT dose of scAAV9-JeT-GANopt (ranging from 3.5x10¹³ vector genomes (vg) to 3.5x10¹⁴ vg total dose) with concomitant immunomodulation protocols. Safety is the primary outcome measure with follow-up data spanning 24-72 months post gene transfer. Secondary outcome measures include the motor function measure (MFM)-32, nerve conduction studies, and nerve pathology. Here we review safety and immunologic findings related to dose, genotype, baseline AAV9 seropositivity, and the use of T-cell immune modulation. We present preliminary efficacy results on change in MFM-32 at one year post gene transfer compared to lead-in and our GAN natural history data as well as MFM-32 trajectories in long-term follow-up. Neurophysiologic (CMAP and SNAP amplitude) and nerve pathology findings are also reviewed. This study highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer and demonstrates the ability of IT gene transfer to positively modify the expected rate of decline and progression in GAN. Importantly, this study serves as proof of concept for IT gene transfer with targeted immune modulation as a successful strategy for gene replacement in disorders affecting the central and peripheral nervous system.