The Biostatistics Center (BC) for Leber's Hereditary Optic Neuropathy (LHON): Gene Therapy Clinical Trial will continue its collaboration with Dr. John Guy, escalating to higher doses of the AAV-ND4 gene therapy investigational product (IP) in this Phase 1 clinical trial. LHON is a maternally inherited blinding disease of mitochondrial DNA (G11778A mutation in the ND4 gene). Dr. Guy has developed a method for allotopic expression, which is a procedure to introduce a ?nuclear version? of this mitochondrial gene and to then target the cytoplasmically synthesized protein to the mitochondria with a mitochondrial targeting sequence. The LHON Gene Therapy Clinical Trial is a Phase 1 clinical trial to evaluate the safety of an open-label, unilateral, single-dose of intravitreal injection of adenoassociated viral vector (AAV-ND4) LHON patients. The BC provides biostatistical and coordinating center support for the study. The BC investigators are an experienced team, who have been involved with ophthalmological clinical trials since 1985 and collaborated with Dr. Guy on a prospective funded natural history study of a cohort of LHON families, which included affected patients and carriers. In the previous funding cycle of this Phase I dose escalation trial, the BC played a critical role in initiating the trial and ensuring compliant enrollment and post injection follow up of 19 patients, 18 of which demonstrated safety of the low and medium dose AAV-ND4 IP. It is also responsible for data quality, management, and entry into the 21 CRF part 11 compliant database. This effort led to the publication of two reports in the peer-reviewed ophthalmology literature. The study team now proposes to employ its procedures, developed, implemented, and proven for the low and medium doses, to escalation of higher doses
Mutations in mitochondrial DNA lead to a spectrum of diseases. The most common mitochondrial disorder is the blinding disease LHON for which no effective treatment exists. Having previously demonstrated safety of low and medium dose AAV-ND4 gene therapy investigational product for LHON patients, we propose to continue dose escalation to higher doses. 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.
