By Doug Macron
After making a number of changes to its pipeline since it was spun out of CytRx in early 2007, RXi Pharmaceuticals is poised to select its first therapeutic candidate before the end of the year, the company's top official told RNAi News last week.
And while the company's inflammatory disease program, which involves oral siRNA delivery, remains its most advanced, a newer effort with RNAi molecules that do not require a delivery vehicle could potentially yield the investigational drug lead, RXi President and CEO Tod Woolf said.
He declined to provide specific details on the selection process, but noted that a decision would be "based on the data."
Since its founding (see RNAi News, 1/11/2007), RXi has tweaked its pipeline at least three times — most recently in March when it named inflammatory disease as its top focus while putting work in neurological disorders, namely amyotrophic lateral sclerosis, on the backburner (see RNAi News, 3/26/2009).
Driving the company's interest in inflammation is a newly licensed delivery technology called glucan-encapsulated siRNA particles, or GERPs, which harness a natural phagocytic process to carry the siRNAs through the intestine and into macrophages (see RNAi News, 10/16/2008).
Under normal conditions, when a macrophage has taken up an antigen, it begins producing cytokines, which in turn triggers inflammation. But a macrophage treated with an anti-inflammatory siRNA would, in theory, lessen inflammation as it migrates from the intestine to other tissues in the body.
According to Woolf, RXi aims to use the GERP technology to target the tumor-necrosis factor-alpha pathway, which is involved in a variety of diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis, although the company has not specified a lead indication for the program.
But while this effort remains the company's top priority, work with so-called self-delivering rxRNAs — RXi refers to all its proprietary RNAi molecules as rxRNAs — could quickly move to the forefront, he suggested.
Specific details about sd-rxRNAs, however, have not been made public yet, partly because RXi isn't entirely clear on how the molecules function, Woolf said.
In its current embodiment, the technology comprises three undisclosed chemical modifications being tested with RXi's nano-rxRNAs, which are duplexes less than 15 base pairs long.
"You can use all three of [the modifications, or] you can use pairs of them; we haven't explored all the combinations," he said. Two of the modifications appear to facilitate self-delivery, while the third one may require at least one of the other two modifications to work.
"The stability of the compound [and] the activity … are all affected by the modifications, too, so it is somewhat hard to tease about what's going on in some cases," Woolf added. "Right now, we're at the stage of figuring out the optimal formulation."
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What is clear is that the sd-rxRNAs are capable of entering all of the cell types RXi has tested.
"If you put them into cell culture, they'll get into any cell type, even the most hard-to-transfect cell type," Woolf said. In in vivo testing, meanwhile, delivery of the molecules seems to be limited only by bio-distribution.
"For example, if you put these in culture with neurons, they'll get into neurons," he said. However, if injected intravenously, sd-rxRNAs would be unable to penetrate the blood-brain barrier, for example.
Overall, though, "once they get into a tissue, there is … spontaneous uptake in the cells that make contact … [and] we think they get into any cell type they [come] into contact with," he noted.
Still, "we don't exactly how [the technology] works," Woolf said. But "they get inside the cell … [and] we have confocal microscopy of live cells showing them in the cytoplasm and [showing target] knockdown."
For all RNAi delivery technologies, "the big issue is getting through the [cell] membrane," he added. "That's the trick that some people who aren't really into the oligo field miss.
"When you're outside the cell, you've got to get through the membrane," he said. "If you're … transcytosed [in any way], you're still on the wrong side of the membrane [because] you're not in the cytoplasm. Breaching the membrane is a trick, and these do that."
With the self-delivering technology, either used locally or systemically, RXi has opened the door to a variety of new indications that it can pursue, including one in an "undisclosed compromised skin indication" that Ramani Varanasi, RXi's vice president of business development, touched on at the Cambridge Healthtech Institute's RNA Interference Summit earlier this month.
In addition, the technology could enable alternate delivery routes — subcutaneous as opposed to intravenous — that could potentially improve dosing and patient compliance issues, Woolf noted.