Emerging therapies for mitochondrial disorders

Nightingale H, Pfeffer G, Bargiela D, Horvath R, Chinnery PF. Emerging

therapies for mitochondrial disorders. Brain. 2016 Jun;139(Pt 6):1633-48.

Abstract

Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.

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From the article

A recent systematic review identified over 1300 reports using a variety of approaches expected to bypass or enhance components of mitochondrial function. However, the vast majority of these reports are open-labelled case series with less than five subjects. Although ~30 randomized trials have been carried out to date, no treatment has shown a clear cut benefit on a clinically meaningful end-point . It is therefore likely that components of the traditional 'mitochondrial cocktail' do not have a major therapeutic impact on most mitochondrial diseases. There is therefore a clear need for the field to 'think outside the box' when developing new treatments, harnessing the massive increase in our understanding of mitochondrial disease pathogenesis…

The delivery of wild-type nDNA  or mtDNA  using viral vectors is another possibility, or perhaps the replacement of dysfunctional proteins via the cell nucleus, hitch-hiking on the mitochondrial import mechanism. Moving away from the two genomes, small molecule screens may enhance function of the respiratory chain, stem cell therapies could correct enzyme defects due to nuclear gene defects, and treatments aimed at non-specifically preventing neurodegeneration may be the way forward…

As for all potential therapies, the multi-organ nature of mitochondrial disorders and difficulties of transferring therapies across cellular and mitochondrial membranes without causing toxic effects, makes therapeutic targeting difficult. However, as explored further below, methods exist to overcome these difficulties including the use of viral vectors, harnessing allotopic expression (nuclear expression of mtDNA encoded protein), or fusion of therapeutic molecules to targeting proteins…

Customized ZFNs [zinc finger nucleases] targeted to mitochondria cause shifts in heteroplasmy through the selective degradation of mtDNA containing the m.8993T > G point mutation, and the large scale (4977 bp) mtDNA 'common deletion', which is the most common cause of chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Pearson marrow pancreas syndrome. This work opens up the opportunity to develop a library of bespoke ZFNs against more common pathogenic mtDNA mutations, but the shifts in heteroplasmy have been limited to date. Longer-term studies, particularly using animal models, will hopefully show that ZFNs can improve biochemical function in vivo—but this will be technically demanding, not least because of the challenges delivering these agents at an appropriate concentration to affected tissues…

Sequence-specific peptide nucleic acids selectively bind mutant mtDNA and induce direct mtDNA strand degradation. Although conjugation with mitochondrial targeting peptides promotes importation and successful targeting into human cells in culture, this initially failed to modulate heteroplasmy in patient-derived cell lines… Although these examples show promise, evidence for therapeutic benefit remains sparse despite nearly two decades of research. Targeted delivery will be a common problem, and potential toxic effects need to be excluded in long-term animal studies. Again, limited availability of animal models of human mtDNA diseases has hindered progress…

Of particular interest are tRNA synthetases that catalyse the addition of specific amino acid molecules to cognate tRNA molecules during protein translation. Early work demonstrated that the overexpression of cognate aminoacyl mt-tRNA synthetase stabilized mt-tRNA (mitochondrial tRNA) molecules…

Harnessing viral vectors to transfer wild-type genes into the cell nucleus dates back to the late 1990's. Although initial excitement was tempered by the death of a patient in an early clinical trial, much progress has been made in developing new, less immunogenic vectors such as AAV…

In vitro and preclinical evidence support the therapeutic potential of increasing deoxyribonucleotides to treat rate autosomal recessive mtDNA depletion syndromes…

Studying a new treatment in a range of cellular and animal systems will reduce the chance of inappropriately rejecting a treatment based on adverse effects in one model. On the other hand, studying more than one model will reduce the chance of pursuing a drug that will never make it into clinical use…

Future pharmaceutical development focusing on disease-specific or patient-specific molecular targets aimed at boosting residual mitochondrial function is likely to be more successful than previous approaches, which were generally based on a non-specific bypass or amelioration of defective components of the respiratory chain…

Interestingly, a recent retrospective analysis of all the 24 patients with MNGIE known to undergo a haematopoietic stem cell transplantation between 2005 and 2011 reported that in the nine survivors, thymidine phosphorylase activity rose from undetectable to normal levels…

From a clinical perspective, nuclear-genetic enzyme defects show the greatest promise. Stem cell therapy is already being used in specific contexts, and its efficacy and safety being evaluated, and gene therapy trials in mouse models show clear benefits.

http://www.medscape.com/viewarticle/864814_7