Preclinical Research Shows Promising New Way to Increase Progranulin in the Brain

Preclinical studies using a new Protein Transport Vehicle (PTV) to cross the blood-brain barrier (BBB) may offer a new way to treat certain types of frontotemporal degeneration (FTD). The research also provided new information about the molecular and cellular system that may contribute to FTD.

Researchers from Denali Therapeutics developed PTV as a way to increase the brain’s intake of progranulin. This could possibly enable increasing the progranulin levels in persons with FTD-GRN, who have a shortage of this protein.

Persons with mutations in the GRN gene usually experience decreased levels of progranulin. This is one of the top known genetic causes of FTD.

Denali announced on March 9, 2022, that dosing began in a Phase 1/2 clinical trial of DNL593 (PTV:PGRN) for the potential treatment of FTD caused by mutations in the granulin gene. Read more here.

Historically, scientists have found it difficult to find a way to get drugs to reach the brain. PTV:PGRN was created to bind receptor molecules that exist on certain cells of the BBB. While they normally transport iron into the brain, PTV:PGRN was used to deliver progranulin into the brains of mice. Research in these progranulin-deficient mice showed that progranulin replacement therapy with PTV:PGRN rescued both neurodegeneration and microglial dysfunction, according to the study’s published summary.

In addition to establishing a new way for progranulin to reach the brain, the research offered insight into how lysosomes are impacted by progranulin deficiencies. These strategies may offer an effective way to increase progranulin levels in lysosomes for the potential treatment of people with FTD-GRN.

Denali announced the publication of these findings in the September 2, 2021, issue of Cell of preclinical proof of concept for using its PTV to enhance brain uptake of peripherally administered progranulin (PTV:PGRN).

“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.”

Denali Therapeutics Inc. is a biopharmaceutical company that is developing various products to cross the blood-brain barrier (BBB) for neurodegenerative diseases.