alpha-tocotrienol-quinone and idebenone

To discuss recent advances in potential treatments for Leber hereditary optic neuropathy (LHON), a typically visually devastating hereditary optic neuropathy caused by mutations in the mitochondrial genome.. Idebenone has been proposed as a means of bypassing defective complex I activity and a free radical scavenger to prevent oxidative damage. EPI-743 may have more potency than idebenone, but no clinical trials have been performed. Gene therapy techniques have advanced significantly, including allotopic expression and nuclear transfer. Successful rescue of animal models of LHON with both of these therapies has been demonstrated. Introduction of exogenous DNA into the mitochondrial genome with mitochondrial targeting of viral vectors is another promising technique.. There are currently no proven treatments for LHON. However, there are many promising novel treatment modalities that are currently being evaluated, with several clinical trials underway or in the planning stages. Supportive measures and genetic counseling remain of great importance for these patients.

Topics: Animals; Genetic Counseling; Genetic Therapy; Humans; Mitochondria; Optic Atrophy, Hereditary, Leber; Ubiquinone

Treatment of mitochondrial respiratory chain (MRC) disorders is extremely difficult, however, coenzyme Q10 (CoQ10) and its synthetic analogues are the only agents which have shown some therapeutic benefit to patients. CoQ10 serves as an electron carrier in the MRC as well as functioning as a potent lipid soluble antioxidant. CoQ10 supplementation is fundamental to the treatment of patients with primary defects in the CoQ10 biosynthetic pathway. The efficacy of CoQ10 and its analogues in the treatment of patients with MRC disorders not associated with a CoQ10 deficiency indicates their ability to restore electron flow in the MRC and/or increase mitochondrial antioxidant capacity may also be important contributory factors to their therapeutic potential.

Topics: Animals; Ataxia; Humans; Mitochondrial Diseases; Molecular Structure; Muscle Weakness; Treatment Outcome; Ubiquinone

Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

Topics: Antioxidants; Arginine; Clinical Trials as Topic; Creatine; Exercise Therapy; Humans; Mitochondrial Diseases; Ubiquinone