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 Intravenous Administration
Denali Therapeutics (DNLI) has published groundbreaking research in Science Translational Medicine, showcasing the potential of their Oligonucleotide Transport Vehicle (OTV) platform. This innovative technology enables broad biodistribution of antisense oligonucleotides (ASOs) in the central nervous system (CNS) and muscle following intravenous administration.
The OTV platform, an extension of Denali's clinically validated Transport Vehicle (TV) technology, addresses a major challenge in oligonucleotide therapeutics: crossing the blood-brain barrier (BBB). Unlike current methods requiring invasive delivery, the OTV allows for uniform distribution throughout the brain via less invasive intravenous administration.
Key findings demonstrate the OTV's ability to provide cumulative and sustained knockdown of target gene expression across multiple CNS regions and cell types, as well as in peripheral muscle tissues. This breakthrough could significantly advance the development of treatments for neurodegenerative and lysosomal storage diseases.
Denali Therapeutics (DNLI) ha pubblicato ricerche rivoluzionarie in Science Translational Medicine, evidenziando il potenziale della loro Piattaforma di Trasporto Oligonucleotidico (OTV). Questa tecnologia innovativa consente una ampia biodistribuzione degli oligonucleotidi antisenso (ASOs) nel sistema nervoso centrale (CNS) e nei muscoli dopo somministrazione endovenosa.
La piattaforma OTV, un'estensione della tecnologia di Trasporto Clinicamente Validata (TV) di Denali, affronta una delle principali sfide nella terapia con oligonucleotidi: superare la barriera emato-encefalica (BBB). A differenza dei metodi attuali che richiedono consegne invasive, l'OTV consente una distribuzione uniforme in tutto il cervello attraverso somministrazioni endovenose meno invasive.
I risultati chiave dimostrano la capacità dell'OTV di fornire un riduzione cumulativa e sostenuta dell'espressione genica target in diverse regioni del CNS e tipi di cellule, così come nei tessuti muscolari periferici. Questa scoperta potrebbe sviluppare in modo significativo i trattamenti per le malattie neurodegenerative e di stoccaggio lisosomiale.
Denali Therapeutics (DNLI) ha publicado investigaciones innovadoras en Science Translational Medicine, destacando el potencial de su Plataforma de Vehículos de Transporte de Oligonucleótidos (OTV). Esta tecnología innovadora permite una biodistribución amplia de oligonucleótidos antisentido (ASOs) en el sistema nervioso central (CNS) y en los músculos tras la administración intravenosa.
La plataforma OTV, una extensión de la tecnología de Vehículo de Transporte clínicamente validada (TV) de Denali, aborda un gran desafío en las terapias con oligonucleótidos: cruzar la barrera hematoencefálica (BBB). A diferencia de los métodos actuales que requieren una entrega invasiva, la OTV permite una distribución uniforme en todo el cerebro a través de la administración intravenosa menos invasiva.
Los hallazgos clave demuestran la capacidad de la OTV para proporcionar un corte acumulativo y sostenido de la expresión génica objetivo en múltiples regiones del CNS y tipos celulares, así como en tejidos musculares periféricos. Este avance podría significar un avance significativo en el desarrollo de tratamientos para enfermedades neurodegenerativas y de almacenamiento lisosómico.
Denali Therapeutics (DNLI)는 Science Translational Medicine에 혁신적인 연구 결과를 발표하여 올리고뉴클레오타이드 운반 차량(OTV) 플랫폼의 잠재력을 보여주었습니다. 이 혁신적인 기술은 항센스 올리고뉴클레오타이드(ASOs)를 정맥 투여 후 중추 신경계(CNS) 및 근육에 광범위하게 분포시킬 수 있게 해줍니다.
OTV 플랫폼은 Denali의 임상 검증된 운반 차량(TV) 기술의 확장으로, 올리고뉴클레오타이드 치료의 주요 문제인 혈액-뇌 장벽(BBB)을 넘는 것을 해결합니다. 현재의 침습적 전달 방법과는 달리, OTV는 덜 침습적인 정맥 투여를 통해 뇌 전체에 균일한 분포를 가능하게 합니다.
주요 발견은 OTV가 여러 CNS 영역과 세포 유형에서 목표 유전자 발현을 누적적이며 지속적으로 줄일 수 있는 능력을 제공한다는 것을 증명하며, 말초 근육 조직에서도 효과적입니다. 이 혁신은 신경퇴행성 질환 및 리소좀 저장 질환 치료제 개발에 상당한 진전을 가져올 수 있습니다.
Denali Therapeutics (DNLI) a publié des recherches révolutionnaires dans Science Translational Medicine, mettant en avant le potentiel de leur plateforme de véhicule de transport d'oligonucléotides (OTV). Cette technologie innovante permet une biodistribution large d’oligonucleotides antisens (ASOs) dans le système nerveux central (CNS) et les muscles après administration intraveineuse.
La plateforme OTV, qui est une extension de la technologie de véhicule de transport validée cliniquement (TV) de Denali, s'attaque à l'un des principaux défis des thérapies par oligonucleotides : franchir la barrière hémato-encéphalique (BBB). Contrairement aux méthodes actuelles qui nécessitent une livraison invasive, l'OTV permet une distribution uniforme dans tout le cerveau par administration intraveineuse moins invasive.
Les résultats clés montrent la capacité de l'OTV à fournir une réduction cumulative et soutenue de l'expression génique cible dans plusieurs régions du CNS et types de cellules, ainsi que dans les tissus musculaires périphériques. Cette avancée pourrait considérablement faire progresser le développement de traitements pour les maladies neurodégénératives et de stockage lysosomal.
Denali Therapeutics (DNLI) hat bahnbrechende Forschung in Science Translational Medicine veröffentlicht und das Potenzial ihrer Oligonukleotid-Transportplattform (OTV) hervorgehoben. Diese innovative Technologie ermöglicht eine widfete Biodistribution von Antisense-Oligonukleotiden (ASOs) im zentralen Nervensystem (CNS) und in der Muskulatur nach intravenöser Verabreichung.
Die OTV-Plattform ist eine Erweiterung der klinisch validierten Transporttechnologie (TV) von Denali und adressiert eine der größten Herausforderungen in der Oligonukleotidtherapie: das Überwinden der Blut-Hirn-Schranke (BBB). Im Gegensatz zu den derzeitigen, invasiven Methoden erlaubt die OTV eine gleichmäßige Verteilung im gesamten Gehirn durch weniger invasive intravenöse Verabreichung.
Wesentliche Erkenntnisse zeigen, dass die OTV in der Lage ist, eine kumulative und anhaltende Herabsetzung der Zielgenexpression in mehreren CNS-Regionen und Zelltypen sowie in peripheren Muskelgeweben zu bieten. Dieser Durchbruch könnte die Entwicklung von Behandlungen für neurodegenerative und lysosomale Speicherkrankheiten erheblich vorantreiben.
- Successful demonstration of broad ASO biodistribution in CNS and muscle via intravenous administration
- Potential to replace invasive intrathecal delivery methods with less invasive intravenous administration
- Uniform distribution of ASOs throughout the brain, addressing a key challenge in CNS drug delivery
- Cumulative and sustained knockdown of target gene expression across multiple CNS regions and cell types
- Successful targeting of peripheral muscle tissues, including skeletal and cardiac muscle
- Extension of clinically validated Transport Vehicle (TV) platform to oligonucleotide delivery
- None.
Insights
This publication in Science Translational Medicine marks a significant advancement in oligonucleotide delivery technology. Denali's Oligonucleotide Transport Vehicle (OTV) platform demonstrates broad biodistribution of antisense oligonucleotides (ASOs) in the CNS and muscle via intravenous administration, a less invasive method than current intrathecal delivery.
The ability to achieve uniform distribution throughout the brain and target multiple cell types, including neurons and glia, is a game-changer for treating neurological disorders. This could potentially improve efficacy and reduce side effects associated with localized high concentrations from direct CNS delivery. The additional benefit of targeting skeletal and cardiac muscle expands the platform's therapeutic potential to neuromuscular diseases.
However, long-term safety and efficacy in humans remain to be established. The transition from non-human primates to clinical trials will be important to validate these promising results.
Denali Therapeutics' OTV platform represents a potentially disruptive technology in the oligonucleotide therapeutics market. With three TV-enabled programs already in clinical development, this publication adds credibility to their approach and could attract partnership opportunities or increase investor interest.
The platform's versatility in delivering various therapeutic cargoes (antibodies, enzymes, proteins and now ASOs) across the blood-brain barrier positions Denali favorably in the competitive neurodegenerative disease space. This could lead to an expanded pipeline and multiple shots on goal, potentially de-risking the company's overall portfolio.
However, it's important to note that while preclinical data is promising, clinical success is not guaranteed. Investors should monitor the progress of Denali's OTV programs for Alzheimer's and Parkinson's diseases, as these will be critical in validating the platform's value and potential market impact.
SOUTH SAN FRANCISCO, Calif., Aug. 14, 2024 (GLOBE NEWSWIRE) -- 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 Platform
The 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 Therapeutics
Denali 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 Reporters
More 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 Statements
This 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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