Towards a therapy for mitochondrial disease: an update

Abstract

Preclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field.

Keywords: bypass therapy; gene therapy; mitochondrial biogenesis; mitochondrial dysfunction; rapamycin.

Figure 1.. Development of new therapies for mitochondrial disorders.

Preclinical (in vivo and in vitro), clinical and drug approval stages are represented in the figure. Note the lack of preclinical data in mitochondrial disease models for some new or re-purpose therapies. Treatments are also divided into ‘general action' or ‘disease target'. When clinical trials have been initiated, the clinicaltrial.gov code number is provided with the potential therapeutic indication. MM, mitochondrial myopathy; MD, mitochondrial disorder; LHON, Leber hereditary optic neuropathy; Tk2, thymidine kinase 2 deficiency; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes; PS, Pearson syndrome; Red arrow, gene therapy; Green arrow, drug approval process; Blue arrow, drug compound; *= GMP product development.

Figure 2.. Scheme of the mTORC1-dependent metabolic pathways.

Figure 3.. Regulation of the hypoxic response by stabilization of HIF1α.

In normoxic conditions, HIF1α is hydroxylated by PH, ubiquitinated by the VHL, and thus targeted to the proteasome for degradation. During hypoxia, PH-dependent hydroxylation is blocked and HIF1α stabilized, thus activating the hypoxic transcriptional response. PH, prolyl hydroxylase; VHL, von Hippel–Lindau factor; Ub, ubiquitin.

Figure 4.. Representation of the main dNTP metabolic pathways.

Catabolic enzymes are marked in orange boxes. ADA, adenosine deaminase; CDA, cytidine deaminase; dAdo, deoxyadenosine; dCK, deoxycytidine kinase; dCtd, deoxycytidine; dCTD, deoxycytidylate deaminase; dGK, deoxyguanosine kinase; dGuo, deoxyguanosine; dIno, deoxyinosine; dThd, thymidine; dUrd, deoxyuridine; ENT1, equilibrative nucleoside transporter 1; PNP, purine nucleoside phosphorylase; RNR, ribonucleotide reductase; THU, tetrahydrouridine; TK1, thymidine kinase 1; TK2, thymidine kinase 2; TP, thymidine phosphorylase; TS, thymidylate synthase. The dNTP precursors used in experimental setups to correct mtDNA instability are marked in yellow. The mitochondrial dNTP pools are marked in green. The enzymes are marked in orange.