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Quieting disease. siRNA molecules like the one shown here (purple and green coils) may treat an inherited liver illness, a new study reports.

Laguna Design/Science Source

RNAi Treatment Steps Up

RNA interference (RNAi), a technique for silencing genes that shows potential for treating diseases, has been like a hot baseball prospect who hasn’t proven he can play in the big leagues. But now RNAi has turned in a performance that is winning researchers’ praise. A new study shows that the approach can dramatically and safely cut levels of a protein that causes a rare liver disease.

Our cells rely on RNAi—deploying diminutive RNA molecules such as microRNAs and small interfering RNAs (siRNAs)—to turn down activity of specific genes. Researchers only discovered this process in the late 1990s, but they’ve already begun dozens of clinical trials to gauge whether infusing patients with these small RNAs works against a range of diseases, from lung infections to liver cancer to age-related macular degeneration, a sight-stealing condition that mainly affects people over the age of 50. Although some results are promising, what remains unclear is whether an effective dose of RNAi will also be safe, says nucleic acid biologist Mark Kay of Stanford University in Palo Alto, California.

In the new work, neurologist Teresa Coelho of the Hospital de Santo Antonio in Portugal and colleagues tested RNAi in patients who had transthyretin amyloidosis, a fatal genetic disease in which liver cells pump out excess amounts of a protein called transthyretin. Normally, transthyretin ferries hormones through the blood, but the extra protein builds up in the nerves, the heart, and elsewhere in the body. Although liver transplants can lengthen the lives of some patients, the disease remains incurable.

The team infused 24 transthyretin amyloidosis patients with an siRNA that curbs cells’ production of the protein. Because RNA-destroying enzymes prowl the spaces between our cells, the siRNAs were tucked inside tiny lipid droplets, known as lipid nanoparticles. Control patients received an infusion of saline. Using a group of healthy subjects, the researchers also tested a slightly different lipid nanoparticle that carried the same siRNA.

In the transthyretin amyloidosis patients, siRNA treatment cut transthyretin levels by 38% after 7 days, the researchers report online today in The New England Journal of Medicine. The healthy patients who received the alternative lipid nanoparticles showed an even bigger decrease, averaging as much as 87%. Those results reveal that liver cells absorbed the lipid nanoparticles and the siRNAs inside turned down transthyretin output. Coelho calls this an “important reduction” in the protein, though the researchers didn’t determine whether siRNA slowed the progress of the disease. They will be measuring that in a 15-month follow-up study that will take place in the United States, Europe, and South America.

Some patients developed allergylike reactions, with symptoms such as flushing and chest tightness. But these problems usually went away if the delivery of the nanoparticles was stopped and then resumed at a slower pace, Coelho says.

The study “unambiguously shows that you can achieve a robust [protein decrease] in humans using RNAi therapeutics,” Kay sats. “This opens the door to medicinal RNAi,” adds molecular biologist David Corey of the University of Texas Southwestern Medical Center in Dallas.

siRNAi therapy could also work against other liver diseases, says molecular geneticist John Rossi of City of Hope in Duarte, California. But he cautions that “since the lipid carriers primarily target the liver, it is not apparent to me if nonliver based diseases can be treated in a similar fashion.”

Controlling diseases such as transthyretin amyloidosis would presumably require multiple treatments over several years, so researchers also need to find out if the siRNA and lipid nanoparticle combination is safe over the long term, Kay says.