Biostatistics Center for Leber's Hereditary Optic Neuropathy: Gene Therapy Trial

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DESCRIPTION (provided by applicant): Our goal in this application is to provide biostatistical and data management support for testing safety of AAV-mediated delivery of the human ND4 gene in a phase I clinical trial of patients with mutated G11778A mtDNA and then move to a Phase II study to prove efficacy in the later years of this program. Phase I will consist of an open-label, unilateral, single-dose intravitreal injection of AAV-ND4 per patient in the worse eye in a dose-escalation study investigating the safety of three vector doses (5x10e9 vg, 2.46x10e10 vg and 1x10e11 vg) in a small number of patients with molecularly confirmed G11778A-mutated mitochondrial DNA who have chronic bilateral, severe visual loss for more than 1 year (Aim 1) or acute bilateral several visual loss for less than 1 year (Aim 2), and then, lastly, in the eye with better vision but that we know is predestined to lose significant vision within 6 months from the onset of visual loss in the first eye (Aim 3). The Biostatistics Center (BC) for Leber's Hereditary Optic Neuropathy (LHON): Gene Therapy Clinical Trial will collaborate with Dr. John Guy to implement this Phase 1 clinical trial. LHON is a maternally inherited blinding disease caused by the G11778A mutation in mitochondrial DNA that affects the ND4 gene of complex I of the respiratory chain. Our group has developed a method for allotropic expression, which is a procedure to introduce a "nuclear version" of this mitochondrial gene and to then target the cytoplasmically synthesized protein into the mitochondria with a mitochondrial targeting sequence. The role of the Biostatistics Center will be to support this tria with regard to development and implementation of trial procedures, data entry, and report generation; to confirm eligibility criteria of participants; ensure data security; and liaise with he Data and Safety Monitoring Committee.