Five years ago, as much of pharma began leaving neuroscience, three big-name scientists from Genentech and some A-list investors, including ARCH and Flagship, made a $217 million bet that new genetic insights and a reliance on biomarkers could bring them success. They called it Denali Therapeutics.

Still, Denali faced the problem that neuroscience developers have faced for decades: How do you get a large molecule across the blood-brain barrier, a natural defense evolved precisely to keep them out? Enzyme replacement therapy, for instance, would be a great candidate to treat several neurological disorders, but enzymes cant cross the barrier.

Now, Denali thinks theyve solved the problem, or at least part of it. In a pair of papers published inScience Translational Medicine,the South San Francisco biotech detailed the invention of a new transport vehicle to sneak large molecules past the brains gates. So far, its been used in mice and monkeys, but they wont wait long to bring it to patients: A clinical trial using it to replace an enzyme lost in people with Hunters syndrome is set to begin this year, with proof-of-concept data expected to come before 2021.

The blood-brain barrier consists in part of tightly packed endothelial cells. Since certain molecules, such as insulin, cross the barrier by first binding to receptors on these cells and then being allowed through, scientists have long tried to build antibodies that can similarly bind to these receptors and shuttle across a therapeutic cargo. But the results, over several decades, have been less than transformative.

CEO and founder Ryan Watts has been part of that search since his Genentech days. The research method he and Denalis scientists came up with began with a process called directed evolution in which a protein is induced to mutate repeatedly, until it gives rise to a protein with the qualities you want to build a protein, called an FC fragment, that binds to whats called a transferrin receptor, a node that normally imports iron into the brain. In theory, there are numerous drugs one could then hook onto that Fc fragment, but Denali first tested it with an antibody-targeting enzyme called beta-secretase. The enzyme is linked to the build-up of amyloid plaques in people with Alzheimers, and the researchers showed their vehicle reduced the amount of amyloid in mice and monkeys.

In a second study, the researchers attached an enzyme called iduronate-2-sulfatase, the critical protein that people with Hunters syndrome are missing. Without it, sugars called glycosaminoglycans build up in cells, causing abnormalities in several different organs. Shire gained approval for an enzyme replacement therapy in 2006, but it only works outside the brain (the companys erstwhile efforts to improve cognitive function yielded little promise). Using the transport vehicle, though, Denali was able to get significantly increased brain penetration of the enzyme and reduce the pathology in mice and monkeys.

Denali played up the potential versatility of their approach over other blood-brain-barrier-crossing proposals, such as bispecific antibodies, saying you can attach a greater range of therapies to their vehicle. The company has over a dozen programs including a Parkinsons one now in the clinic but the first test of the vehicle will be later this year, in 16 kids with a rare disease whose worst symptoms remain untreated.

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Denali unveils new way of crossing blood brain barrier as the big neuroscience bets enter its clinical years - Endpoints News