MERRF and MELAS: current gene therapy trends and approaches

Abstract

This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. How to cite this article: Agresti CA, Halkiadakis PN, Tolias P. MERRF and MELAS: current gene therapy trends and approaches. Abstract The mitochondrion is a unique organelle that predominantly functions to produce useful cellular energy in the form of adenosine triphosphate (ATP). Unlike other non-nuclear eukaryotic organelles (with the exception of chloroplasts), mitochondria have two lipid membranes that enclose their own mitochondrial DNA (mtDNA) and ribosomes for protein production. Similar to nuclear DNA, mtDNA is equally susceptible to mutations that may be classified as either pathogenic or nonpathogenic. Myoclonic Epilepsy with Ragged Red Fibers (MERRF) and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) are mitochondrial diseases originating from pathogenic point mutations located within mtDNA. Currently, there is no cure and patient care primarily focuses on treating each disease's associated symptoms. When considering the multiple barriers existing between the extracellular surface of the plasma membrane and the location of the mtDNA within the mitochondrial matrix, developing a pharmacological therapeutic that can both overcome these barriers and correct an mtDNA causing mitochondrial disease remains difficult at best. Interestingly, the field of gene therapy may provide an opportunity for effective therapeutic intervention by introducing a genetic payload (to a particular cellular gene) to induce the correction. This review primarily focuses on understanding the principles of mitochondrial biology leading to the mtDNA diseases, MERRF and MELAS, while providing a landscape perspective of gene therapy research devoted to curing these diseases.