New company aims RNA-based therapies at neurological, metabolic disease.

Neil Savage

A biotech company that is less than two years old is on the verge of going public, taking advantage of the excitement around RNA interference–based therapeutics. It also helps that one of its scientific founders won the Nobel Prize for the discovery of the gene-silencing mechanism.

RXi Pharmaceuticals, of Worcester, MA, was founded as a subsidiary of the Los Angeles–based biopharmaceutical company CytRx, with $17 million in funding from CytRx and another $17 million from other investors. Its mission is to develop therapies based on RNA interference (RNAi) for a wide range of diseases, from neurodegenerative to metabolic diseases. One of RXi’s founders, Craig Mello of the University of Massachusetts Medical School, won a Nobel Prize last year for his pioneering work on RNAi.

In October, the company filed a registration statement with the Securities and Exchange Commission to spin off as a public company from CytRx, which focuses on a different class of drugs. RXi is awaiting SEC approval before going public.

Silence that gene

RXi aims to make use of small interfering RNAs—short segments of RNA a couple of dozen nucleotides in length—that the company believes will act as drugs to shut down genes involved in certain diseases. One disease they’re targeting is an inherited form of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. People with a mutated form of the SOD1 gene account for only one to two percent of patients with the debilitating disease, but studies in mice by two of the company’s scientific advisors at UMass suggest that down-regulating that gene can delay the onset of ALS. “In principal you could treat [patients] ahead of time and stop them from ever getting the disease,” says Tod Woolf, CEO of RXi.

The company is also looking at type II diabetes, which is often associated with obesity. They’ve identified a series of genes that, when inhibited in mice, increase metabolism and combat obesity. One of the company’s cofounders, Michael Czech of UMass Medical School, found that when he deleted one of these genes, mice on a high-fat diet stayed lean and didn’t develop diabetes. RXi wants to develop a RNA-based drug that silences this gene.

All of the company’s work is still in early discovery stages, and Woolf wouldn’t predict when a treatment might make it into the clinic, though it will likely be several years.

RNA race

RXi has a formidable competitor: Alnylam Pharmaceuticals, of Cambridge, MA, has taken an early lead in developing a number of therapies. It already has one treatment, for a respiratory virus, in phase II clinical trials.

But Woolf says RXi, which is targeting different diseases than Alnylam, has some advantages of its own. “One thing that makes us stand out is our intellectual property, which is licensed since 2003 and goes all the way back to the beginning of RNAi,” he says. They have exclusive licenses to pending patents from UMass and Imperial College London and a number of nonexclusive licenses as well.

Another key advantage, says Woolf, is a delivery mechanism for getting the small RNAs where they want them to go, a key challenge that all RNA drug developers face. RXi cofounder Tariq Rana of UMass Medical School has developed nanoparticles and shown that when they are mixed with small RNA molecules, they bind to the RNA to form tiny particles that migrate to the liver in mice–an important target when treating metabolic diseases—without getting flushed out of the body by the kidneys.

“There’s great hope, but whether [an RNA-based drug] actually comes into routine clinical use is something nobody can predict,” says Manjunath Swamy of Harvard’s Immune Disease Institute,an affiliate of Harvard Medical School formerly called the CBR Institute for Biomedical Research. Swamy has developed a technique for transporting small RNAs across the blood-brain barrier.

Swamy says that, with so many potential targets for RNAi therapies, there’s plenty of room for both Alnylam and RXi, as well as other companies.