Electrophysiologic and histologic findings following intrathecal AAV9 mediated gene transfer for giant axonal neuropathy

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. Based on an ongoing natural history study (NCT01568658), we report on electrophysiologic data on motor and sensory amplitude responses in 40 participants with GAN with at least one nerve conduction study recording. We report on single time point and longitudinal trends in motor and sensory nerve amplitude as compared to age. Electrical impedance myography of four upper and four lower limb muscles has also been obtained. Concurrently, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for the treatment of GAN was initiated (NCT02362438). This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes, with concomitant immunosuppression. Findings for up to six years post gene transfer included stable or re-emerging sensory amplitudes for digit II median sensory (n=5) and digit V ulnar sensory (n=6) nerves. Of note, the stability or recovery as was seen in upper extremity sensory responses contrasts with more variability that was observed in motor responses. Post gene transfer, the following additional measures were reported: electrical impedance myography, nerve pathology (regenerative cluster density), and epidermal nerve fiber layer density. Together, these data suggest dose, age, and length dependent nerve restoration following IT AAV9 gene therapy and suggest that additional evidence of positive clinical impact could be expected if patients were treated at a younger age or earlier in disease course. Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. Based on an ongoing natural history study (NCT01568658), we report on electrophysiologic data on motor and sensory amplitude responses in 40 participants with GAN with at least one nerve conduction study recording. We report on single time point and longitudinal trends in motor and sensory nerve amplitude as compared to age. Electrical impedance myography of four upper and four lower limb muscles has also been obtained. Concurrently, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for the treatment of GAN was initiated (NCT02362438). This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes, with concomitant immunosuppression. Findings for up to six years post gene transfer included stable or re-emerging sensory amplitudes for digit II median sensory (n=5) and digit V ulnar sensory (n=6) nerves. Of note, the stability or recovery as was seen in upper extremity sensory responses contrasts with more variability that was observed in motor responses. Post gene transfer, the following additional measures were reported: electrical impedance myography, nerve pathology (regenerative cluster density), and epidermal nerve fiber layer density. Together, these data suggest dose, age, and length dependent nerve restoration following IT AAV9 gene therapy and suggest that additional evidence of positive clinical impact could be expected if patients were treated at a younger age or earlier in disease course.