Development of pharmacological strategies for mitochondrial disorders

Abstract

Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application.

Recognition, investigation and management of mitochondrial disease

“…Excessive production of reactive oxygen species occurs when the respiratory chain is dysfunctional, and it is thought that consequent oxidative stress may play an important role in the pathophysiology of mitochondrial disorders 35. Numerous antioxidants have been used in the treatment of mitochondrial diseases.…”

Emerging concepts in the therapy of mitochondrial disease

“…pre-clinical) therapies for mitochondrial disease. Ongoing clinical trials have recently been reviewed elsewhere [15].…”

“…Cocktails of antioxidant compounds, including lipoic acid, vitamins C and E, and CoQ, have extensively been used in the therapy of mitochondrial diseases for a long time, but no quantitative studies have been carried out in animal models to validate their use. Likewise, randomized double blind trials are still missing to support their efficacy in patients [1,15]. In addition, although a transgenic mouse overexpressing a mitochondrially-targeted catalase shows increased lifespan and resistance to oxidative damage [64], the efficacy of antioxidants in cellular and/or animal models of OXPHOS defects is still controversial.…”

The Mitochondrial Disease Narp Syndrome in the Practice of a Pediatric Neurologist

“…Опубликовано несколько небольших рандо-мизированных контролируемых исследований по ис-пользованию коэнзима Q10, высоких доз убихинона (5 мг / кг / сут), витамина Е, рибофлавина, карнитина, диметилглицина, ацетилцистеина и дихлорацетата на-трия, однако клинический эффект данных препаратов сомнителен [5,12,15].…”