GAN is a rare and fatal pediatric neurodegenerative disorder affecting the central and peripheral nervous system. Recessive variants in the GAN 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 2nd to 3rd decade of life. 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. Fourteen GAN participants have been dosed at four dose levels (ranging from 3.5×10^13 vector genomes (vg) to 3.5×10^14 vg per patient) with scAAV9-JeT-GANopt, with concomitant immunomodulation protocols. Follow up data up to 72 months post gene transfer has been collected. We review here safety and immunologic findings related to dose, genotype, baseline seropositivity, and the use of T-cell immune modulation. We present here interim efficacy results of the primary outcome measure, change in motor function measure (MFM-32) at one year post gene transfer compared to the annual decline in MFM-32 score observed in the natural history study, and also present long-term changes in MFM-32 following IT gene transfer. We review secondary efficacy measures including neurophysiologic (CMAP and SNAP amplitude), pathology findings, and markers of visual function post gene transfer. This study highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer. This study demonstrates the ability of IT gene transfer to positively modify the observed rate of decline and progression in GAN and 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.