- 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
Precision BioSciences, Inc. (Nasdaq: DTIL), an advanced gene
editing company utilizing its novel proprietary ARCUS® platform to
develop in vivo gene editing therapies for sophisticated gene
edits, including gene insertion, excision, and elimination, today
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).
“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
Jeff Smith, Ph.D., Chief Research Officer of Precision BioSciences.
“Today’s publication further validates the ability of ARCUS to
overcome the limitations of CRISPR-based gene editing technologies
for treating mitochondrial disease and eliminating mutated
mitochondrial DNA with high specificity to improve overall
mitochondrial function. Furthermore, these data highlight our
ability to design ARCUS nucleases to discriminate a single
nucleotide change between the mutant and wild-type DNA sequence,
even at very high dose levels. These data strengthen our conviction
in PBGENE-PMM as a novel therapy for primary mitochondrial
myopathies and we look forward to advancing this program towards an
anticipated clinical trial application (CTA) and/or investigational
new drug (IND) filing in 2025.”
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 Carlos Moraes, PhD, Esther Lichtenstein
Professor of Neurology, and Cell Biology and Anatomy at the
University of Miami Miller School of Medicine. “This exciting
development has the potential to bring a curative treatment for
patients suffering from m.3243 associated primary mitochondrial
myopathy and the ARCUS technology can potentially be applied to
other mitochondrial diseases in the future.”
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.
About Precision BioSciences, Inc.
Precision BioSciences, Inc. is an advanced gene editing company
dedicated to improving life (DTIL) with its novel and proprietary
ARCUS® genome editing platform that differs from other technologies
in the way it cuts, its smaller size, and its simpler structure.
Key capabilities and differentiating characteristics may enable
ARCUS nucleases to drive more intended, defined therapeutic
outcomes. Using ARCUS, the Company’s pipeline is comprised of in
vivo gene editing candidates designed to deliver lasting cures for
the broadest range of genetic and infectious diseases where no
adequate treatments exist. For more information about Precision
BioSciences, please visit www.precisionbiosciences.com.
Forward-Looking Statements
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,”
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“pursue,” “should,” “target,” “will,” “would,” or the negative
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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
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and our product candidates; the U.S. and foreign regulatory
landscape applicable to our and our collaborators’ development of
product candidates; our or our collaborators’ or other licensees’
ability to advance product candidates into, and successfully
design, implement and complete, clinical or field trials; our or
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candidates into, and successfully design, implement and complete,
clinical or field trials; potential manufacturing problems
associated with the development or commercialization of any of our
product candidates; delays or difficulties in our and our
collaborators’ ability to enroll patients; changes in interim
“top-line” and initial data that we announce or publish; if our
product candidates do not work as intended or cause undesirable
side effects; risks associated with applicable healthcare, data
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therewith; the rate and degree of market acceptance of any of our
product candidates; the success of our existing collaboration
agreements, and our ability to enter into new collaboration
arrangements; our current and future relationships with and
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our ability to obtain and maintain intellectual property protection
for our technology and any of our product candidates; potential
litigation relating to infringement or misappropriation of
intellectual property rights; our ability to effectively manage the
growth of our operations; our ability to attract, retain, and
motivate key executives and personnel; market and economic
conditions; effects of system failures and security breaches;
effects of natural and manmade disasters, public health emergencies
and other natural catastrophic events; effects of sustained
inflation, supply chain disruptions and major central bank policy
actions; insurance expenses and exposure to uninsured liabilities;
effects of tax rules; risks related to ownership of our common
stock; our ability to meet the requirements of and maintain listing
of our common stock on NASDAQ or other public stock exchanges and
other important factors discussed under the caption “Risk Factors”
in our Quarterly Report on Form 10-Q for the quarterly period ended
September 30, 2023, as any such factors may be updated from time to
time in our other filings with the SEC, which are accessible on the
SEC’s website at www.sec.gov and the Investors page of our website
under SEC Filings at investor.precisionbiosciences.com.
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.
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Investor and Media Contact: Mei Burris Senior Director of
Finance and Controller Mei.Burris@precisionbiosciences.com
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