Precision BioSciences, Inc. announced publication in the journal Nature Metabolism of a peer reviewed manuscript titled ?Efficient elimination of MELAS-associated m.3243G mutant mitochondrial DNA by an engineered mitoARCUS nuclease.? This publication includes preclinical research supporting continued development of the PBGENE-PMM in vivo gene editing program as a potentially curative therapeutic approach for patients with m.3243-associated primary mitochondrial myopathy (PMM). The Nature Metabolism publication highlights the development of a mitochondrial-targeted ARCUS nuclease, mitoARCUS, which is designed to specifically target and cleave the pathogenic m.3243G point mutation.

Using cells that contained 95% mutant m.3243G mtDNA, mitoARCUS was found to eliminate all of the mitochondrial DNA containing the mutation, leaving the wild-type or normal mitochondrial DNA untouched. This wild-type mitochondrial DNA was then able to be rapidly replicated by the cell in order to maintain a steady mitochondrial DNA copy number. By eliminating the mutant mitochondrial DNA and allowing the wild-type mitochondrial DNA to repopulate, mitoARCUS drives a shift toward healthy mitochondrial DNA, a process known as shifting heteroplasmy.

About Mitochondria and Primary Mitochondrial Myopathy: Mitochondria contain multiple copies of a circular DNA molecule, referred to as mtDNA, which are necessary to support mitochondrial function and the production of energy. Due to the multi-copy nature of the genome, mutations often exist in a state known as heteroplasmy in which both mutant and wild-type genomes are present in the same cell. The presence of the wild-type molecules offsets the impact of the mutant ones until a particular disease threshold is reached.

Unlike the nuclear DNA which is repaired following double-strand breaks, there is no efficient double-strand break repair mechanism in mitochondria and any genomes that are linearized will be rapidly degraded. A tightly controlled mechanism for maintaining mitochondrial DNA copy number results in the replication of any remaining genomes following a depletion. Therefore, nuclease-induced double-strand breaks in mutant mitochondrial DNA molecules can lead to shifts in mitochondrial DNA heteroplasmy.

It is believed that a shift in mitochondrial DNA heteroplasmy toward wild-type (normal) may provide therapeutic benefit for patients, and not all mutant mitochondrial DNA must be eliminated to achieve improvements in symptoms. Rather, mutant mitochondrial DNA levels only need to be shifted below the disease threshold. Mitochondrial diseases that arise from mutations in mitochondrial DNA are the most common hereditary metabolic disorder, affecting 1 in 4,300 people. Primary mitochondrial myopathy is characterized by severe fatigue and can affect skeletal muscle, and other high energy organs such as the brain, eyes, ears and heart.

Primary mitochondrial myopathy currently lacks curative treatment and impacts approximately 50% of patients with mitochondrial disease. About PBGENE-PMM: The high specificity and simple, single component nature of Precision?s mitoARCUS nucleases are designed to enable specific editing to eliminate mutant mitochondrial DNA while allowing wild-type (normal) mitochondrial DNA to repopulate in the mitochondria and restore normal function. PBGENE-PMM is a wholly-owned program of Precision BioSciences which is designed to detect a single base pair defect and make a cut in the mutant mitochondrial DNA which results in its elimination.

About ARCUS: ARCUS is a proprietary genome editing technology discovered and developed by scientists at Precision BioSciences. It uses sequence-specific DNA-cutting enzymes, or nucleases, that are designed to either insert (knock-in), excise (knock-out), eliminate, or repair DNA of living cells and organisms. ARCUS is based on a naturally occurring genome editing enzyme, I-CreI, that evolved in the algae Chlamydomonas reinhardtii to make highly specific cuts in cellular DNA and stimulate gene insertion at the cut site by homologous recombination. Precision's platform and products are protected by a comprehensive portfolio including nearly 100 patents to date.