Denali Therapeutics Announces Publication in Cell on New Approach to Treat FTD-GRN
Preclinical studies show enhanced brain uptake of progranulin can be achieved using Denali’s Transport Vehicle to cross the blood-brain barrier
SOUTH SAN FRANCISCO, Calif., Aug. 26, 2021 (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 neurodegenerative diseases, today announced publication of preclinical proof of concept for using its Protein Transport Vehicle (PTV) to enhance brain uptake of peripherally administered progranulin (PTV:PGRN). This approach may have utility in treating certain types of frontotemporal dementia (FTD), especially FTD-GRN caused by progranulin deficiency.
Published Thursday, August 26th, ahead of print in the September 2nd issue of Cell, the preclinical research showed that progranulin replacement therapy with Denali’s PTV:PGRN rescued both neurodegeneration and microglial dysfunction in progranulin-deficient mice. The research also provides new insight into the molecular and cellular mechanisms that may contribute to FTD, identifying novel roles of progranulin in lysosomal function and lipid metabolism, as well as lysosome biomarkers with potential clinical utility.
“This preclinical research demonstrates that our Protein Transport Vehicle can enhance the uptake of peripherally administered progranulin by multiple cell types in the brain, including neurons and microglia,” said Denali’s Chief Scientific Officer Joseph Lewcock, Ph.D. “In addition, the improved mechanistic understanding of progranulin’s role in lysosomal function indicates that our therapeutic strategy with PTV:PGRN may be the most direct and effective way to increase progranulin levels in lysosomes for the potential treatment of people with FTD-GRN.”
PTV:PGRN is engineered to bind transferrin receptor molecules, which are present in large amounts on endothelial cells of the BBB and normally function to transport iron into the brain. This approach enables PTV:PGRN to be actively transported into the brain, potentially overcoming a long-standing challenge to the field of delivering protein therapeutics across the BBB.
New insights on the role of progranulin and effects of PTV:PGRN in preclinical models of FTD
Mutations in the GRN gene, which encodes the progranulin protein, generally result in reduced protein levels of progranulin and are amongst the most common genetic causes of FTD. The studies published in Cell used two common models of FTD-GRN, genetically engineered progranulin-deficient mice as well as iPSC-derived human microglial cells, to investigate the role of progranulin and effects of PTV:PGRN treatment on disease pathology.
The preclinical research showed that lysosomes – which function as the “digestive system” of cells – are the primary cellular organelles impacted by progranulin deficiency. A new finding revealed in the preclinical studies was that progranulin regulates lysosomal function through binding to and stabilizing a lysosome-specific lipid, bis(monoacylglycero)phosphate (BMP), which is critical for normal lysosomal function.
In the progranulin-deficient mice, BMP lipid levels were profoundly decreased, which resulted in reduced activity of the lipid-metabolizing enzyme glucocerebrosidase (GCase) and accumulation of the GCase substrate glucosylsphingosine (GlcSph); GCase is known to be involved in Gaucher disease and GBA-linked Parkinson’s disease. A mild decrease in BMP and an increase in GlcSph was also found in biofluid samples from patients with FTD, with or without GRN mutations.
Treatment of progranulin-deficient mice or human cells with PTV:PGRN was sufficient to rescue a range of lysosomal defects, including BMP deficiency, GlcSph accumulation, lysosomal vacuolization and lysosomal membrane damage. In addition, PTV:PGRN corrected lipofuscinosis, microgliosis and astrogliosis, which are common disease-relevant brain pathologies in progranulin-deficient mice that are also present in patients with FTD-GRN.
“Collectively, these new insights from our preclinical research suggest that FTD-GRN may be an atypical lysosomal storage disorder, and that lysosomal function can be restored by PTV:PGRN,” said Dr. Lewcock. “Our work also identified candidate clinical biomarkers indicative of lysosomal dysfunction, such as BMP and GlcSph, which may help to evaluate the future therapeutic efficacy of PTV:PGRN and other therapeutics in people with FTD-GRN.”
“Publication of this research in Cell marks a significant milestone in the development of therapeutics enabled by our Transport Vehicle technology,” said Denali’s Chief Executive Officer Ryan Watts, Ph.D. “We are making great progress towards our goal of initiating clinical testing of our lead PTV:PGRN molecule (DNL593) and believe that our unique brain-penetrant progranulin replacement approach has the potential to make a difference for individuals and their families affected by FTD-GRN.”
About Denali’s TV Platform
The 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 CNS 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 fragments that bind to specific natural transport receptors, such as transferrin receptor, which are expressed at the BBB and deliver TV and its therapeutic cargo to the brain through receptor-mediated transcytosis. In animal models, antibodies and enzymes engineered to the TV technology demonstrate more than 10- to 30-fold greater brain exposure than similar antibodies and enzymes 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.
About Denali Therapeutics
Denali Therapeutics is a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases. Denali pursues new treatments by rigorously assessing genetically validated targets, engineering delivery across the BBB and guiding development through biomarkers that demonstrate target and pathway engagement. Denali is based in South San Francisco. For additional information, please visit
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 PTV:PGRN, plans regarding planned future clinical studies of PTV:PGRN (DNL593), expectations regarding Denali’s TV technology platform, the therapeutic potential of PTV:PGRN (DNL593) and Denali’s TV platform, and statements made by Denali’s Chief Scientific Officer and Chief Executive Officer. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: Denali’s early stages of clinical drug development; Denali’s and its partners’ ability to complete the development and, if approved, commercialization of PTV:PGRN (DNL593); Denali’s and its partners’ ability to enroll patients in its ongoing and future clinical trials; Denali’s reliance on third parties for the manufacture and supply of its product candidates for clinical trials; the potential for clinical trial results of PTV:PGRN (DNL593) to differ from preclinical or expected results, the risk that results from early preclinical biomarker studies will not translate to clinical benefit in clinical studies; and that PTV:PGRN (DNL593) may not receive regulatory approval as a treatment of FTD-GRN necessary to be commercialized. 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 26, 2021, and August 4, 2021, 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.
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