Emerging therapies for mitochondrial disorders

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.

Keywords: gene therapies; mitochondrial disorders; pharmaceuticals; protein; treatment.

Traditionally, mitochondrial disorders have been treated with vitamins, co-factors and nutritional supplements with no proven benefit. While effective treatments are still lacking, several new molecular and cellular strategies have recently been proposed. Nightingale et al. critically appraise the most promising preclinical developments.

Figure 1

Overview of novel therapeutic approaches for the treatment of mitochondrial disorders. AICAR = 5-aminoimidazole-4-carboxamide ribonucleotide; PAPR = poly adenosine diphosphate-ribose polymerase receptor; TP = thymidine phosphorylase.

Figure 2

Endonucleases. Endonucleases are used to target specific sequences in mtDNA causing double-strand breaks and degradation of mtDNA. For example the endonuclease ZFN has been shown to reduce mutation load in a cybrid model of Leigh and NARP syndrome, which are caused by the mtDNA mutation m.8933T > G within the ATP6 domain. ZFN binds specifically to the mutant form of the mtDNA and the FOK1 endonuclease domain cleaves the DNA molecule, which is then degraded.

Figure 3

Adeno-associated viral vectors expressing wild-type gene constructs. Gene constructs can be introduced into host cells by AAV and transcribed within the nucleus of the host. The end product is a functional protein, which can replace or bypass dysfunctional proteins resulting from mutations in the host’s nDNA or mtDNA.

Figure 4

Schematic representation of pharmaceutical modulators of mitochondrial biogenesis. There are multiple signalling pathways involved in mitochondrial biogenesis. PGC-1α (encoded by PPARGC1A), which is a co-activator for a family of transcriptional factors known as PPARs, co-ordinates via a cascade of nuclear encoded proteins the vast majority transcriptional mitochondrial biogenesis. Novel pharmacological therapies aim to modulate PCG-1α mtDNA expression (e.g. PPARα) and protein expression or target downstream pathways. Bezafibrate is pharmacological ligand for the transcriptional co-factor PGC-1α. AICAR activates AMP-activated protein kinase (AMPK) and is thought to modulate increased mitochondrial biogenesis through PGC-1α. The natural polyphenol resveratrol activates sirtuin 1 (SIRT1). Sirtuins are part of a group of oxidizing NAD-dependent protein deacetylases. Upon activation, for example, by PGC-1α or transcription factor A, mitochondrial (TFAM) they promote mitochondrial respiratory chain activities and the transcription of genes modulating mitochondrial biogenesis and function. Nicotinamide riboside can be used to supplement NAD+ levels. PARP1 functions as a NAD+ consuming enzyme. Thus in turn inhibition of PARP1 has been demonstrated to increase NAD+ bioavailability and SIRT1 activity (not shown above) promoting oxidative phosphorylation. Rapamycin inhibits mTOR, which in turn releases mTOR inhibition of autophagy. Cyclosporin A inhibits the mitochondrial permeability transition pore (MPTP). Opening of the mitochondrial permeability transition pore is thought to deplete pyridine nucleotides thus impairing mitochondrial oxidative respiration.

Figure 5

Mechanism of action of stem cell therapies. Various mechanisms have been described for the therapeutic action of stem cells for neurodegenerative conditions. These include secretion of neurotrophic factors and antioxidant enzymes such as superoxide dismutase, modulation of the immune system, regeneration of neurons and more controversially, stem cell transdifferentiation into neurons. Recently mesenchymal stem cells have been demonstrated to fully fuse with native cells to form heterokaryons or partially fuse via junction formation and transfer cellular organelles and factors.