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RNA-Based Cholesterol Drug Is Readied for Human Tests

New methods for delivering the therapies to the target tissue could boost a wavering field.

A number of drugs can help lower dangerously high cholesterol, but as many as half a million people worldwide are resistant to existing therapies. Alnylam Pharmaceuticals, a leader in the development of therapies using RNA, aims to begin human tests of a treatment that could make a drastic dent in drug-resistant high cholesterol. The company recently filed a clinical trial application to test a new formulation of the drug in 32 U.K. volunteers. It will be the fourth therapy from Alnylam to be tested in humans.

The technology targets an enzyme involved in clearing cholesterol from the blood. A single dose has already been shown to reduce LDL, or “bad,” cholesterol, in nonhuman primates by as much as 50 percent.

Alnylam’s technique coöpts a method of gene silencing employed by our own cells. It uses short lengths of small interfering RNA (siRNA) to interrupt gene transcription and prevent the production of proteins produced by the gene. The process was first discovered in animals fewer than 15 years ago, and was heralded as a way for drug manufacturers to regulate troublesome, disease-causing genes. Over two dozen such therapies have advanced to early-stage clinical trials.

But progress hasn’t been as fast as pharmaceutical companies had hoped. Last year alone, Roche terminated its program after only three years, and Novartis decided not to spend $100 million to renew its partnership with Alnylam.

One big problem is getting the molecules delivered to the right tissues. Many RNA interference approaches use “naked” siRNA delivered as directly as possible to the relevant tissue, such as the eyes or lungs. But this only works for easy-to-access tissues. In Alnylam’s cholesterol therapy, siRNA is encapsulated into a lipid-based nanoparticle designed to be taken up by liver cells. The siRNA blocks transcription of the gene that produces an enzyme called PCSK9, which binds to LDL receptors on liver cells and prevents them from clearing LDL from the blood.

A new version, developed in collaboration with AlCana Technologies and MIT researchers, uses the same siRNA encapsulated in a nanoparticle that is more effectively taken up by the liver. In animal testing, the second-generation drug was just as effective as the first at a substantially lower dose.

“A few years ago, achieving human systemic delivery was something that was still on the horizon for us,” says Akshay Vaishnaw, Alnylam’s chief medical officer. “But our second-generation nanoparticles have now shown very effective systemic delivery in nonhuman primates in very low doses.”

Alnylam and its collaborators have developed an extensive library of lipids, each with specific properties that can help get their payload to the right tissue. “They have this nice grocery store of [lipid-like molecules] that they can pull off the shelf and test for various indications,” says John Rossi, a researcher at City of Hope in Duarte, California. Rossi was not involved with the research but is working with a competing company on an siRNA treatment for HIV. “I think it’s a great technical improvement in the field,” he says.

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