Precision BioSciences Announces Publication in Nature Metabolism Supporting ARCUS® In Vivo Gene Editing as a Potentially Curative Treatment for Mitochondrial Diseases
- Publication validates unique ability of ARCUS genome editing to preferentially target and eliminate mutant m.3243G mitochondrial DNA (mtDNA) with high specificity
- mitoARCUS efficiently shifted m.3243A>G heteroplasmy without off-target activity, leading to an overall improvement in mitochondrial function
“As a result of attributes that differentiate ARCUS, especially its cut, size, and simplicity as a single-component protein, our strategy is to expand the use of gene editing beyond simple gene knockouts in the liver into more sophisticated edits where ARCUS is uniquely applicable. For mitochondrial diseases, what makes ARCUS such an elegant and simple tool is that it is a single protein that both recognizes and eliminates the mutant mitochondrial DNA,” said
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.
“To date, there are no curative treatments for mitochondrial diseases, so a gene editing approach is a novel way to offer hope to the patients suffering from mitochondrial myopathy. However, many gene editing technologies, especially those derived from CRISPR approaches, have been unable to effectively target mutant mitochondrial DNA because they are complicated by numerous components, so they are not expected to be effective therapeutic options for mitochondrial diseases. The simplicity of mitoARCUS has allowed it to be one of the first approaches to demonstrate an ability to not only distinguish the single nucleotide difference in the m.3243A>G mutation, but also efficiently eliminate the mutation to allow wild-type mtDNA to repopulate within the cell and restore function,” said
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.
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
ARCUS is a proprietary genome editing technology discovered and developed by scientists at
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the therapeutic potential of an ARCUS gene editing approach for the treatment of m.3243-associated PMM, including the ability of ARCUS to preferentially target and eliminate mutant m.3243G mtDNA with high specificity and without off-target activity, anticipated timing of a CTA and/or IND filing, the ability of mitoARCUS to shift heteroplasmy, and expected safety, efficacy, and benefit of our gene editing approaches. In some cases, you can identify forward-looking statements by terms such as “aim,” “anticipate,” “approach,” “believe,” “contemplate,” “could,” “estimate,” “expect,” “goal,” “intend,” “look,” “may,” “mission,” “plan,” “possible,” “potential,” “predict,” “project,” “pursue,” “should,” “target,” “will,” “would,” or the negative thereof and similar words and expressions.
Forward-looking statements are based on management’s current expectations, beliefs and assumptions and on information currently available to us. These statements are neither promises nor guarantees, but involve number of known and unknown risks, uncertainties and assumptions, and actual results may differ materially from those expressed or implied in the forward-looking statements due to various important factors, including, but not limited to: our ability to become profitable; our ability to procure sufficient funding to advance our programs; risks associated with raising additional capital and requirements under our current debt instruments and effects of restrictions thereunder; our operating expenses and our ability to predict what those expenses will be; our limited operating history; the success of our programs and product candidates in which we expend our resources; our limited ability or inability to assess the safety and efficacy of our product candidates; our dependence on our ARCUS technology; the risk that other genome-editing technologies may provide significant advantages over our ARCUS technology; the initiation, cost, timing, progress, achievement of milestones and results of research and development activities, preclinical studies and clinical trials; public perception about genome editing technology and its applications; competition in the genome editing, biopharmaceutical, and biotechnology fields; our or our collaborators’ ability to identify, develop and commercialize product candidates; potential product liability lawsuits and penalties against us or our collaborators related to our technology and our product candidates; the
All forward-looking statements speak only as of the date of this press release and, except as required by applicable law, we have no obligation to update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
Investor and Media Contact:
Senior Director of Finance and Controller