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.
LHON is the most common mitochondrial DNA disorder. It is a blinding disease and no effective treatment exists. We propose to use the AAV vector to deliver the affected ND4 gene to LHON patients. This will be the first gene therapy study for a mitochondrial disease. If we can show this therapy is safe, it may provide an effective treatment for LHON as well as other mitochondrial diseases of the eye and other organ systems.