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- W4238353234 abstract "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. 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. Thirteen 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. We present here a review of safety data in the study, as well as interim study analysis data evaluating efficacy in this study. Outcome measures of interest include: motor function measure 32 (MFM32), neuropathy impairment score (NIS), modified Friedreich Ataxia Rating Scale (mFARS), myometry, and electrophysiologic data. This study highlights the feasibility for targeting the nervous system, and recapitulates the impact of baseline disease severity on efficacy and its importance in patient stratification. We describe the utility of a Bayesian statistical analysis to assess efficacy post gene transfer in an ultrarare disease with a natural history comparator. We further present systematically analyzed immunologic markers including: 1) Analysis of B and T cell responses following an IT gene transfer; 2) Effect of baseline AAV9 seropositive status, 3) Inclusion of biallelic null mutation patients with targeted T cell immune modulation. This study highlights key considerations in the field of gene therapy including: dose safety and feasibility; 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." @default.
- W4238353234 created "2022-05-12" @default.
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- W4238353234 date "2020-10-01" @default.
- W4238353234 modified "2023-10-04" @default.
- W4238353234 title "HEREDITARY NEUROPATHIES & ALS" @default.
- W4238353234 doi "https://doi.org/10.1016/j.nmd.2020.08.112" @default.
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