715. Giant Axonal Neuropathy - The Role of Natural History Studies in Gene Transfer Therapy Trial Design
Authors: Diana Bharucha-Goebel, Minal Jain, Melissa Waite, Tanya Lehky, Reghan Foley, Jonathan D. Marra, Wadih Zein, Carsten G. Bonnemann
Journal: Molecular Therapy (2016)

OBJECTIVE: Giant axonal neuropathy (GAN) is a rare childhood onset autosomal recessive neurodegenerative disorder affecting the central and peripheral nervous system. Mutations in the GAN gene cause loss of function of gigaxonin, a cytoskeletal regulatory protein, clinically leading to progressive sensorimotor neuropathy and neuropathy, reduced coordination, slurred speech, seizures, and progressive respiratory failure leading to death by the 2nd to 3rd decade of life. We are in the midst of a first-in-human intrathecal AAV9 mediated gene transfer trial for GAN. Given the ultra-rare nature of the disease, it is critical to build disease appropriate outcome measures and have lead in safety and outcome data to feed into the clinical trial. Our aim here was to identify and develop targeted quantitative markers of disease severity in GAN. METHODS: This natural history study evaluated measures of motor, neurophysiologic, and ophthalmologic function as well as exploratory neuroimaging markers in genetically confirmed GAN patients seen at the National Institutes of Health (NIH). The primary aim was to correlate a quantitative motor scale (MFM32) with a semi-quantitative Neuropathy Impairment Score (NIS) in cross sectional analysis of GAN patients. Secondary aims included evaluation of strength (myometry) and motor nerve amplitude (nerve conduction) compared to motor function (MFM32). Quantitative ophthalmologic testing included retinal nerve fiber layer thickness analysis correlated to visual acuity, MFM32, and motor nerve amplitude. Additional exploratory measures of spinal cord volume, brain DTI, quantitative MR spectroscopy, and biochemical (in serum and CSF) measures are underway. RESULTS: 15 GAN patients were evaluated at the NIH. Data analysis (Pearson correlation) showed the following: 1) NIS and MFM32 are significantly correlated (p<0.0001); 2) Muscle strength of knee extension, knee flexion, hip abduction, and hand grip each correlate significantly with MFM32 (p values from <0.0001 to 0.039) ; 3) Median motor nerve amplitude correlates significantly with MFM32 (p=0.0016). There was no significant correlation between elbow extension or elbow flexion strength and MFM32. Retinal nerve fiber layer corresponds strongly with MFM32 and the median motor nerve amplitude (p<0.0001 and p=0.005, respectively). CONCLUSIONS: The phase I intrathecal gene transfer study for GAN is a novel clinical trial, and will set a precedent by proof of principle for future gene transfer trials for neurodegenerative disorders. The primary outcome is safety, but given that the trial entails administration of a presumed effective dose, careful selection to outcome measures was essential in the protocol design. Through this natural history study, we have identified markers such as the MFM32, NIS, median motor amplitude, and retinal nerve fiber layer thickness, as well as spinal cord volumetric data that clearly correlate with disease progression. These markers are being followed longitudinally in natural history and were designed into the phase I trial. Such broad data capture allows for the incorporation of more targeted disease specific clinically meaningful outcome measures and data on natural rate of progression of such markers over short durations of follow up. Such models of trial design will be crucial to the development of genetic therapeutic trials for rare neurodegenerative disorders.