Review of ophthalmologic findings following intrathecal gene transfer for giant axonal neuropathy


Clinical Trials

Poster Number: 75


Dimah Saade MD, Diana Bharucha-Goebel MD, Wadih Zein MD, Gina Norato ScM, Denis Rybin , Ken Cheung , Eduardo Paredes , Sara Inati , Steven Gray , Carsten Bönnemann MD


1. National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, 2. National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, 3. National Institutes of Health, National Eye Institute, 4. National Institutes of Health, Clinical Trials Unit, 10. NINDS/NIH, Bethesda, MD

Giant Axonal Neuropathy (GAN) is an ultra-rare childhood onset neurodegenerative disorder of the peripheral and central nervous system. Recessive GAN mutations cause loss of function of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure. We report on the ophthalmologic findings of a single site, phase I, non-randomized, open label dose escalation gene transfer study for GAN (NCT02362438), a first-in-human intrathecal (IT) AAV9 mediated gene transfer. Data from 11 patients with GAN dosed at 3 dose levels; 3.5×1013 (1X), 1.2x 1014 (3.3X), and 1.8×1014 (5X) with scAAV9-JeT-GAN with up to 3 years of follow up is analyzed. Ophthalmic evaluations include best-corrected visual acuity, color discrimination thresholds, fundus imaging, and measurement of retinal nerve fiber later (RNFL) thickness through Optical Coherence Tomography. Photopic electroretinography including a photopic negative response and visual evoked potentials (VEP) were also recorded. GAN natural history study data is used for comparison of visual acuity and RNFL thickness as well as correlation of RNFL thickness with validated outcome measures of motor function. Cross sectional natural history analysis shows significant correlation between RNFL thickness and the MFM32 total score. Interim analysis reveals a trend towards stabilization and slowing of the expected decline in RNFL thickness and visual acuity compared to pre-trial lead in data and natural history. VEP results were variable with no consistent trends across natural history and clinical trial cohorts. The interim analysis of ophthalmologic assessments highlights several key aspects: 1) RNFL thickness, a structural assessment of optic nerve atrophy and axonal nerve degeneration at the level of the CNS is a biomarker strongly correlated to overall disease severity. In GAN patients, the decline in RNFL precedes change in visual acuity, and changes can be detected longitudinally. 2) The trend towards stabilization of RNFL thickness post gene transfer suggests that RNFL may be an objective and responsive biomarker of visual system involvement and overall nervous system degeneration in GAN. 3) Assessment of RNFL thickness post gene transfer may be used as an exploratory marker of feasibility of CNS transduction following IT gene transfer.