Antisense oligonucleotides (ASOs), which bind to RNA and prevent them from being translated into proteins, have gained popularity in recent years as a way to treat neurodegenerative diseases. However, getting these drugs into the brain has been challenging, currently requiring invasive infusion directly into the cerebrospinal fluid.
Now, Denali Therapeutics has developed a way to deliver these drugs to the brain more easily—by smuggling them across the blood-brain barrier. In studies with mice and macaques, the California-based biotech combined ASOs with their transferrin-targeting transport vehicle platform and successfully knocks down certain gene activity across the brain.
“Not only could we get brain uptake, but we could get it into the cell, we could get knock down of the genes that we're interested in,” Denali Chief Scientific Officer Joe Lewcock, Ph.D., told Fierce Biotech in an interview. “Really demonstrating that this platform can be effective for this class of drugs as well.” The results appeared in Science Translational Medicine on Aug. 14.
The blood-brain barrier protects precious gray matter from unwanted intruders, but its stinginess means it excludes helpful drugs from reaching the brain too. Denali’s transport vehicle platform is an engineered antibody that targets transferrin receptor 1, which normally shuttles iron—essential for brain function—across the barrier.
This technology is the basis for the biotech’s lead drug candidate, DNL310, where iduronate 2-sulfatase enzyme is bound to the transport vehicle and shepherded into cells to treat Hunter syndrome. Individuals with the disease have mutations in the gene that codes for the iduronate 2-sulfatase enzyme, making it not work properly. DNL310 is currently in phase 3 trials.
To test the approach with ASOs, Denali scientists chose to focus on a gene called malat1.
“It's a commonly used target in the field for proof-of-concept,” according to Lewcock, and is expressed in all cell types of the central nervous system. Binding an ASO targeting malat1 to Denali's transport vehicle forms an oligonucleotide transport vehicle (OTV), which allows the ASO to be shuttled into diverse cells and can successfully reduce expression of the gene in both mice and cynomolgus macaques.
Lewcock sees three advantages to OTVs. First is the intravenous delivery, which is less invasive than intrathecal infusion directly into the central nervous system. Another benefit is the even distribution of the drug throughout the brain, hitting all cell types, which could mean greater efficacy and—the third advantage—an improved safety profile.
With intrathecal delivery, “to get up to the brain, you have to have very high concentrations in the lumbar spinal cord, and that could cause safety issues,” Lewcock explained. “Even biodistribution allows you to get adequate [amounts of] drug to the right places and avoid that.”
With OTVs having proven their mettle in animal studies, Lewcock said Denali is now pursuing two lead OTV candidates in neurodegenerative disease.
“One's targeting the MAPT gene, or tau, in the context of Alzheimer's disease, and the second is targeting the alpha-synuclein gene in the context of Parkinson's disease,” he explained. “We've done a lot of work on those targets and optimizing molecules for each of those targets.”
The plan is for OTVs to join the broader transport vehicle family, which in addition to enzyme carriers also includes antibody transporters.
“We're really building a foundation with the enzyme transport vehicle franchise,” Denali's vice president of investor relations Laura Hansen, Ph.D., said in a joint interview with Fierce Biotech. “Those near- to mid-term revenues expected from those indications will enable us to really continue to expand the transport vehicle platform opportunities into the antibodies and oligonucleotides.”
Denali intends to seek accelerated approval for DNL310, the company's enzyme-based lead candidate for Hunter syndrome, Hansen added.