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.

Keywords

Mitochondria / mitochondrial biology / mitochondrial DNA / mitochondrial diseases / gene therapy / MERRF / A8344G / MELAS / A3243G

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