Ophthalmologic 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. We have evaluated participants with GAN in an ongoing natural history study (NCT01568658). Additionally, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438) is ongoing. 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 by dot blot, with concomitant immunomodulation. Cross-sectional and longitudinal ophthalmologic data are presented, including best corrected visual acuity (LogMAR) and retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) (SD-OCT: Cirrus HD-OC) from participants with GAN in natural history and in participants following gene transfer. Participants with GAN, especially those with a more aggressive form of the disease, frequently have abnormalities in average RNFL thickness (defined as < 80 μm) and progressive decline in visual acuity. Prior to gene transfer, 9 participants (64%) had abnormal RNFL thickness at baseline in the right (OD) and left eye (OS) (range: 56 - 100 μm). In follow up to 6 years, we observe trends towards stabilization in visual acuity as assessed by slope post gene transfer as compared to lead in natural history data. Concomitant trends in RNFL measurements following gene transfer were reviewed, taking into account the measurable range of RNFL thickness. Potential stabilization in visual acuity over long term follow up suggests an impact at the level of the optic nerve with IT administration of AAV9 mediated gene transfer in GAN at the vector genome doses administered in this trial. 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. We have evaluated participants with GAN in an ongoing natural history study (NCT01568658). Additionally, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438) is ongoing. 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 by dot blot, with concomitant immunomodulation. Cross-sectional and longitudinal ophthalmologic data are presented, including best corrected visual acuity (LogMAR) and retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) (SD-OCT: Cirrus HD-OC) from participants with GAN in natural history and in participants following gene transfer. Participants with GAN, especially those with a more aggressive form of the disease, frequently have abnormalities in average RNFL thickness (defined as < 80 μm) and progressive decline in visual acuity. Prior to gene transfer, 9 participants (64%) had abnormal RNFL thickness at baseline in the right (OD) and left eye (OS) (range: 56 - 100 μm). In follow up to 6 years, we observe trends towards stabilization in visual acuity as assessed by slope post gene transfer as compared to lead in natural history data. Concomitant trends in RNFL measurements following gene transfer were reviewed, taking into account the measurable range of RNFL thickness. Potential stabilization in visual acuity over long term follow up suggests an impact at the level of the optic nerve with IT administration of AAV9 mediated gene transfer in GAN at the vector genome doses administered in this trial.