Impairment of mitochondrial energy metabolism has been associated with a wide range of human disorders. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes) is a relatively common mitochondrial phenotype frequently associated with a point mutation at nucleotide 3243 of the mitochondrial DNA (m.3243A>G), and characterized clinically by progressive neurological decline, multisystem medical problems, and premature death. Over the past 15 years, our team has conducted a large-scale, longitudinal follow-up study in a cohort of MELAS/3243 patients, which has enabled us to establish a strong foundation in terms of data, outcome measures and infrastructure for conducting clinical trials of promising therapeutic agents,, none of which - sadly - has proved effective. Thus, MELAS patients remain without treatment options. To address this unmet need, our primary aim is to conduct a Phase 11/111, multi-center, randomized, placebo controlled clinical trial of SNT-MC17/idebenone, with a statistical global test of health status as primary outcome consisting of 1) neurological event count, 2) daily living functional abilities, 3) neurological exam, and 4) neuropsychological testing. SNT-MC17/idebenone has emerged as highly promising treatment for MELAS because it is a powerful antioxidant and a modulator of adenosine triphosphate (ATP) production and because it has been reported beneficial in a number of mitochondrial disorders including MELAS, Leber's hereditary optical neuropathy (LHON), and Friedreich's Ataxia. We postulate that the clinical effects of SNT-MC17/idebenone will be mediated by improvements of oxidative energy metabolism. To derive objective measures of a treatment effect, we propose to determine in vivo levels of lactate in the cerebral occipital lobe during photic stimulation by [1]H magnetic resonance spectroscopic imaging ([1]H-MRSI) and levels of high-energy phosphates by dynamic [31]P-MRSI, in the calf muscle during exercise. Given the lack of long-term follow-up studies in patients with MELAS/3243, our Specific Aim 3 is to continue collecting longitudinal data on subjects enrolled in our ongoing cohort study.

Public Health Relevance

Our proposal is relevant to three key needs for MELAS/3243 patients. First, it evaluates a promising treatment in a controlled trial, which could ameliorate this devastating disease and reduce the individual and societal burden of MELAS/3243. Second, the proposed MRSI studies of a potential biomarker can provide mechanistic insights into the consequences of idebenone treatment and serve as an early efficacy read-out in future trials, thus potentially accelerating drug development. Third, we will gather long-term follow-up data on our MELAS/3243 cohort, addressing crucial questions that all patients have regarding their prognosis.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Columbia University (N.Y.)
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