Denali reveals new way to deliver antisense oligonucleotides across blood-brain barrier

The blood-brain barrier is a crucial defense mechanism for protecting the brain's gray matter from harmful substances. However, its selective permeability also prevents many beneficial drugs from entering the brain. This has posed significant challenges in treating neurodegenerative diseases with antisense oligonucleotides (ASOs), which are designed to bind to RNA and block protein synthesis. Traditionally, delivering ASOs to the brain has required invasive procedures, such as direct infusion into the cerebrospinal fluid.

Denali Therapeutics, a biotech firm based in California, has developed an innovative method to overcome this obstacle. By using a transferrin-targeting transport vehicle, Denali has successfully delivered ASOs across the blood-brain barrier in mouse and macaque studies. This method effectively reduces specific gene activity within 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," said Denali’s Chief Scientific Officer Joe Lewcock, Ph.D., in an interview. The results of this research were published on August 14 in "Science Translational Medicine."

Denali’s approach utilizes an engineered antibody that targets transferrin receptor 1, which typically transports iron across the blood-brain barrier, essential for brain function. This technology underpins their leading drug candidate, DNL310, designed to treat Hunter syndrome. This rare genetic disorder results from mutations in the gene coding for the iduronate 2-sulfatase enzyme. DNL310 combines this enzyme with the transport vehicle to effectively deliver it into brain cells and is currently undergoing phase 3 clinical trials.

For ASOs, the Denali team chose the gene malat1 as their target. Malat1 is a well-known target in neurodegenerative research and is expressed across all central nervous system cell types. By binding an ASO to the malat1 gene with their transport vehicle, they created an oligonucleotide transport vehicle (OTV). This OTV was shown to reduce gene expression in both mice and cynomolgus macaques successfully.

Lewcock highlighted three key advantages of OTVs. First, they can be administered intravenously, a less invasive method compared to intrathecal infusion into the central nervous system. Second, OTVs allow for the even distribution of the drug throughout the brain, enhancing efficacy. Third, this distribution avoids the high concentrations in the lumbar spinal cord required for intrathecal delivery, potentially reducing safety concerns.

Denali is now advancing two lead OTV candidates for neurodegenerative diseases. One targets the MAPT gene (tau) in Alzheimer's disease, and the other targets the alpha-synuclein gene in Parkinson's disease. Extensive work has been done to optimize molecules for these targets. "We've done a lot of work on those targets and optimizing molecules for each of those targets," Lewcock explained.

Denali aims to integrate OTVs into their broader transport vehicle platform, which includes enzyme carriers and antibody transporters. "We're really building a foundation with the enzyme transport vehicle franchise," said Laura Hansen, Denali's vice president of investor relations. The company plans to seek accelerated approval for DNL310, their enzyme-based candidate for Hunter syndrome, leveraging anticipated revenues to expand their transport vehicle platform into new areas, including antibodies and oligonucleotides.