DURHAM, N.C.–(BUSINESS WIRE)–Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS® genome editing platform, today announced a new paper published online in Nature Communications that reports preclinical results using an ARCUS nuclease to target mitochondrial DNA (mtDNA) and reduce levels of mutant mtDNA in vivo.
The study, “Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo” was led by Carlos T. Moraes, Ph.D., Esther Lichtenstein Professor in Neurology at the University of Miami Miller School of Medicine, with Ugne Zekonyte as first author.
Mitochondrial disorders impair the function of mitochondria, the organelles that produce the energy needed by cells. Organs and tissues that require more energy, such as the heart, muscles and brain, are more often affected. Additionally, both mutant and wild-type mtDNA can co-exist within the mitochondria of a cell, a phenomenon called mtDNA heteroplasmy. When specific threshold levels of mutant mtDNA are reached, cell function can be compromised, and disease can manifest1. It is believed that a shift in mtDNA heteroplasmy toward wild-type may provide therapeutic benefit for patients, and not all mutant mtDNA must be eliminated to achieve improvements in symptoms; mutant mtDNA levels just need to be reduced below the disease threshold level.
“In the past, mitochondrial-targeted nucleases have been successful in shifting mtDNA heteroplasmy but have come with unwanted drawbacks, most notably large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness,” said Dr. Moraes. “In this study, a mitochondrial-targeted ARCUS nuclease (mitoARCUS) used to edit mutant mtDNA was particularly effective, in part because of the nuclease’s small size and single protein nature. We are very excited with this early research and the great promise we believe it suggests for using ARCUS editing in patients with mtDNA diseases in the future.”
Researchers involved with the study reported mitoARCUS-induced heteroplasmic shifts of up to 60% in vitro, with changes persisting for up to three weeks. When tested in a heteroplasmic mouse model, mitoARCUS delivered by AAV effectively shifted heteroplasmy towards wild-type in several of the analyzed tissues of juvenile mice, with no depletion in total mtDNA levels at 6, 12, or 24 weeks. In adult mice treated with AAV-mitoARCUS, there was no editing at any of the potential nuclear off-target sites, and liver and skeletal muscle showed robust elimination of mutant mtDNA with concomitant restoration of mitochondrial transfer RNA levels.
“This is the first time ARCUS has been used to edit outside the nuclear genome and has done so with encouraging safety and efficacy in this mouse model,” said Derek Jantz, Ph.D., co-author of the paper and Chief Scientific Officer at Precision BioSciences. “We continue to see promising results in preclinical studies suggesting that ARCUS could potentially effectively edit mutant mtDNA in vivo in human clinical trials. I congratulate Carlos and his team on this research and look forward to further work on this program.”
Dr. Moraes will discuss this paper during the United Mitochondrial Disease Foundation’s Mitochondrial Medicine 2021 Virtual “Meet the Scientific Program Faculty” on Friday, June 4, 2021 at 12:00 PM EDT.
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), remove (knock-out), 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. Precision’s platform and products are protected by a comprehensive portfolio including more than 75 patents to date.
About Precision BioSciences, Inc.
Precision BioSciences, Inc. is a clinical stage biotechnology company dedicated to improving life (DTIL) with its wholly proprietary ARCUS® genome editing platform. ARCUS is a highly specific and versatile genome editing platform that was designed with therapeutic safety, delivery, and control in mind. Using ARCUS, the Company’s pipeline consists of multiple “off-the-shelf” CAR T immunotherapy clinical candidates and several in vivo gene correction therapy candidates to cure genetic and infectious diseases where no adequate treatments exist. For more information about Precision BioSciences, please visit www.precisionbiosciences.com.
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1 Craven, L., et al., Recent Advances in Mitochondrial Disease. Annu Rev Genomics Hum Genet, 2017. 18: p. 257-275.