Denali Therapeutics Announces Publication in Science Translational Medicine Demonstrating the Potential of the Oligonucleotide Transport Vehicle Platform to Achieve Broad Biodistribution of Antisense Oligonucleotides in the CNS and Muscle Following Intrave
August 14 2024 - 1:00PM
Denali Therapeutics Inc. (Nasdaq: DNLI), a biopharmaceutical
company developing a broad portfolio of product candidates
engineered to cross the blood-brain barrier (BBB) for the treatment
of neurodegenerative and lysosomal storage diseases, today
announced publication of nonclinical data in the August 14, 2024
issue of Science Translational Medicine (link) demonstrating the
ability of the Oligonucleotide Transport Vehicle (OTV) platform to
achieve broad biodistribution of antisense oligonucleotides (ASOs)
in the central nervous system (CNS) and skeletal and cardiac muscle
following intravenous (IV) administration.
Oligonucleotides, such as ASOs, are designed to modify gene
expression and hold promise as therapeutics for neurological
disorders. A major challenge in their development, however, is that
oligonucleotides are unable to cross the BBB on their own.
Currently, oligonucleotides must be delivered directly to the CNS
through invasive routes such as intrathecal delivery and still may
not distribute uniformly throughout the brain where treatment is
needed. Denali invented the Transport Vehicle (TV) platform to
overcome the challenge of the BBB and deliver multiple types of
therapeutic cargo across the BBB, including antibodies, enzymes,
and other proteins. The TV platform has been clinically validated
and three TV-enabled programs are currently in clinical
development.
“This is the first publication of data showing that ASOs can be
delivered uniformly throughout the primate CNS and to muscle via a
less invasive route of intravenous administration enabled by the TV
platform,” said Joseph Lewcock, Ph.D., Chief Scientific Officer of
Denali. “Across modalities, enhanced brain uptake with uniform
distribution throughout the CNS is a defining hallmark of the TV.
Publication of our OTV research is a significant milestone
supporting TV platform expansion as we advance our first two OTV
programs towards the clinic for Alzheimer’s disease and Parkinson’s
disease.”
In the Science Translational Medicine article, Denali scientists
describe using OTV, which is an engineered TV conjugated to an ASO,
for delivery of therapeutic molecules to the mouse and nonhuman
primate brain. The data show that OTV can successfully cross the
BBB following IV administration and provide cumulative and
sustained knockdown of the ASO target gene expression across
multiple CNS regions and all major cell types, including
endothelial cells, neurons, astrocytes, microglia, and
oligodendrocytes. Additionally, OTV enabled knockdown of the ASO
target gene expression in historically difficult to target
peripheral muscle tissues, including skeletal and cardiac muscle.
In comparison to other clinically relevant ASO delivery platforms,
including direct delivery of a non-TV-enabled ASO to the
cerebrospinal fluid, systemic OTV enabled a much more uniform ASO
biodistribution profile and knockdown of the target.
About Denali’s Transport Vehicle PlatformThe
blood-brain barrier (BBB) is essential in maintaining the brain’s
microenvironment and protecting it from harmful substances and
pathogens circulating in the bloodstream. Historically, the BBB has
posed significant challenges to drug development for central
nervous system diseases by preventing most drugs from reaching the
brain in therapeutically relevant concentrations. Denali’s
Transport Vehicle (TV) platform is a proprietary technology
designed to effectively deliver large therapeutic molecules such as
antibodies, enzymes, proteins, and oligonucleotides across the BBB
after intravenous administration. The TV technology is based on
engineered Fc domains that bind to specific natural transport
receptors, such as transferrin receptor and CD98 heavy chain amino
acid transporter, which are expressed at the BBB and deliver the TV
and its therapeutic cargo to the brain through receptor-mediated
transcytosis. In animal models, antibodies and enzymes engineered
with the TV technology demonstrate more than 10- to 30-fold greater
brain exposure than similar antibodies and enzymes without this
technology. Oligonucleotides engineered with the TV technology
demonstrate more than a 1,000-fold greater brain exposure in
primates than systemically delivered oligonucleotides without this
technology. Improved exposure and broad distribution in the brain
may increase therapeutic efficacy by enabling widespread
achievement of therapeutically relevant concentrations of product
candidates. The TV platform has been clinically validated and three
TV-enabled programs are currently in clinical development.
About Denali TherapeuticsDenali Therapeutics is
a biopharmaceutical company developing a broad portfolio of product
candidates engineered to cross the blood-brain barrier for
neurodegenerative diseases and lysosomal storage diseases. Denali
pursues new treatments by rigorously assessing genetically
validated targets, engineering delivery across the blood-brain
barrier, and guiding development through biomarkers that
demonstrate target and pathway engagement. Denali is based in South
San Francisco. For additional information, please visit
www.denalitherapeutics.com.
Special Note to ReportersMore information,
including a copy of the paper, can be found online at
the Science Translational Medicine press package
at https://www.eurekalert.org/press/medpak/.
Cautionary Note Regarding Forward-Looking
StatementsThis press release contains forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Forward-looking statements expressed or implied
in this press release include, but are not limited to, statements
regarding Denali's plans, timelines, and expectations related to
its OTV programs and planned clinical trials; Denali's expectations
regarding the therapeutic potential of its TV platform; and
statements made by Denali's Chief Scientific Officer. Actual
results are subject to risks and uncertainties and may therefore
differ materially from those indicated by these forward-looking
statements, including due to risks related to: Denali’s dependence
on successful development of its BBB platform technology and
TV-enabled product candidates; Denali’s ability to conduct or
complete clinical trials on expected timelines; the risk of
significant adverse events, toxicities, or other undesirable side
effects; the risk that results from early clinical biomarker
studies will not translate to clinical benefit in late clinical
studies; developments relating to Denali’s competitors and its
industry; Denali’s ability to obtain, maintain, or protect
intellectual property rights; and other risks and uncertainties. In
light of these risks, uncertainties, and assumptions, the
forward-looking statements in this press release are inherently
uncertain and may not occur, and actual results could differ
materially and adversely from those anticipated or implied in the
forward-looking statements. Accordingly, you should not rely upon
forward-looking statements as predictions of future events.
Information regarding additional risks and uncertainties may be
found in Denali’s Annual and Quarterly Reports on Forms 10-K and
10-Q filed with the Securities and Exchange Commission (SEC) on
February 28, 2024 and August 1, 2024, respectively, and Denali’s
future reports to be filed with the SEC. Denali does not undertake
any obligation to update or revise any forward-looking statements,
to conform these statements to actual results, or to make changes
in Denali’s expectations, except as required by law.
Investor and Media Contact: Laura Hansen, Ph.D.
Vice President, Investor Relations (650) 452-2747
hansen@dnli.com
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