RARE Daily

Papers Show Ability of Denali Technology to Carry Therapeutic Proteins Across the Blood-Brain Barrier

May 28, 2020

Denali Therapeutics published two papers in Science Translational Medicine that describe the company’s transport vehicle technology and its ability to transport therapeutic proteins across the blood-brain barrier.

Photo: Ryan Watts, CEO of Denali Therapeutics

The blood-brain barrier is essential in maintaining the brain’s microenvironment and protecting it from harmful substances and pathogens circulating in the bloodstream. But the barrier has also posed a challenge to drug developers seeking to treat diseases of the central nervous system 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. In animal models, antibodies and enzymes engineered with the TV technology have demonstrated more than 20-fold greater brain exposure than similar antibodies and enzymes without this technology. Improved exposure and broad distribution in the brain may enable higher, therapeutically relevant concentrations of product candidates, and thus increase therapeutic efficacy.

The papers show Denali’s ability to deliver therapeutic proteins to the brain at levels sufficient for robust effects and demonstrate the normalization of biomarkers in a disease model of Hunter syndrome, a lysosomal storage disorder also known as MPS II.

The first paper describes the development and engineering of the TV platform and demonstrates how it increases brain exposure and distribution of certain antibodies in preclinical models including non-human primates. The second paper describes the applicability of the TV platform in delivering the lysosomal enzyme iduronate 2-sulfatase (IDS) across the BBB, with more than 20-fold improved brain exposure and distribution throughout the brain. The administration of IDS using the TV technology in in vivo models leads to complete correction of downstream disease-relevant pathologies, including accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage.

Hunter Syndrome is caused by a deficiency of the IDS enzyme. Approximately two-thirds of patients with Hunter Syndrome suffer from progressive cognitive impairment in addition to other severe clinical manifestations. Standard enzyme replacement therapy does not result in sufficient brain concentrations to adequately address cognitive impairment.

Denali is developing DNL310, a recombinant form of the IDS enzyme engineered to cross the blood-brain barrier using Denali’s proprietary enzyme transport vehicle (TV) technology. DNL310 is administered intravenously and intended to improve overall clinical manifestations of Hunter Syndrome, including neurological symptoms, which are not adequately addressed by currently approved therapies.

“Taken together, these papers demonstrate the potential of our protein engineering approach, describe in vivo proof-of-concept studies for the TV platform in mice and non-human primates, and illustrate the application of the TV technology to enzymes for the treatment of lysosomal storage diseases,” said Ryan Watts, CEO of Denali Therapeutics. “The peer-review and publication of these papers are important independent examinations of our platform and approach.”

Author: Rare Daily Staff

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