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Oral RNAi Drug Stops Inflammation in Mice, RXi Says

The big challenge in the field of RNA interference drugs is with how to deliver them effectively through the body. Now scientists at the University of Massachusetts Medical School are reporting today in Nature they have come up with an oral pill form of this gene-silencing approach, which passed an early test in mice.

If this technology can show the same kind of effect in people—always a big if—then it could be a boon to Worcester, MA-based RXi Pharmaceuticals (NASDAQ: RXII), which has an exclusive license to the technology. The senior author of the paper is Michael Czech, a researcher at UMass Medical School, and co-founder and scientific adviser to RXi.

The problem of how to deliver RNA interference drugs has been around since the technique was co-discovered a decade ago by another one of RXi’s founders, UMass researcher and Nobel Laureate Craig Mello. These drugs are thought to have the advantage of being able to specifically hit targets on cells that other drugs can’t, and to get at the genetic root cause of disease. The problem is that small interfering RNA drugs can get chewed up by enzymes in the body, or flushed through the kidneys long before they ever get to the diseased cells. Some leading RNAi companies, like Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY) have tried to work around this with locally-delivered drugs that don’t have to circulate through the body, or with lipid nanoparticle capsules designed to protect the drug in the body until it gets to the diseased cells.

Czech’s technique to avoid this problem, as I first explained in this November feature, is to package an RNA interference molecule with a beta-glucan particle in an oral pill that disguises it to look like yeast to the body. Once the package goes through the digestive tract, surviving stomach acids, it encounters transporter proteins in the lining of the gut that carry it across the tissue membrane, where it comes into contact with macrophage cells. These cells, which play a role in inflammation, gobble up the cloaked form of the drug, which can then send signals internally to decrease activation of the macrophages.

“Oral administration of RNAi therapeutics using this particular technology is a major scientific breakthrough that was not previously thought practical,” said Tod Woolf, RXi’s CEO, in a statement. “It now appears that this method may constitute a significant advance in RNAi delivery.”

Czech and his colleagues showed that they could silence a gene for TNF alpha, an inflammatory protein that plays a role in autoimmune diseases like rheumatoid arthritis, and is the target of multi-billion dollar drugs like Amgen’s etanercept (Enbrel) and Abbott Laboratories’ adalimumab (Humira).

The research was paid for by the National Institutes of Health and UMass Medical Center.

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