Taking advantage of a delivery technology acquired in 2002, Baxter Healthcare is collaborating with researchers from Harvard Medical School’s Immune Disease Institute to develop a locally delivered siRNA-based drug for herpes simplex virus type II, RNAi News has learned.
According to IDI researcher Judy Lieberman, her lab has been working with Baxter to develop the company’s Promaxx microsphere technology for delivering siRNAs targeting nectin-1, a receptor for HSV infection.
The investigators used the microspheres to deliver cholesterol-conjugated siRNAs against green fluorescent protein into the vaginal epithelium and lamina propria of GFP transgenic mice, triggering tissue-specific target silencing. They presented their findings in a poster at the fourth annual meeting of the Oligonucleotide Therapeutics Society held this month in Boston.
“We then looked at silencing a putative host viral receptor — nectin-1 — in a dose-response experiment,” the team wrote in the poster’s abstract. Intravaginal “administration of formulated siRNA effectively knocked down nectin-1 expression in the genital tract … [forming] the basis for ongoing in vivo investigations.”
Lieberman said that the next step for the collaborators is to determine how long siRNAs formulated with the Promaxx technology can protect mice against HSV infection, with the goal of at least reaching the one-week mark achieved in an earlier study by Lieberman and collaborators at Alnylam Pharmaceuticals that used unformulated siRNAs.
She noted that a paper describing the work done with Alnylam is currently being prepared for publication. Previously, Lieberman’s group reported that an siRNA/lipid mixture delivered directly into the vagina could protect mice from lethal HSV type II infection.
“So far what we showed [through the Baxter collaboration] is that we get good delivery [and] we get very good silencing in the genital tract,” she said. “What we’re doing now is to see if we can get the kind of protection we got without … formulated siRNAs.”
“So far what we showed [through the Baxter collaboration] is that we get good delivery [and] we get very good silencing in the genital tract. What we’re doing now is to see if we can get the kind of protection we got without … formulated siRNAs.”
While Lieberman sees formulation strategies as being key for RNAi-based therapeutics in certain instances, she said that she wasn’t certain that one would be required for an siRNA drug locally delivered to mucosal surfaces — in this case the vaginal epithelium.
“I’m not completely certain what the advantages of the formulation will be,” she said. “They could be more stability in vitro … shelf-life stability … or longer half-life in vivo. I’m not sure yet. That’s what we’re [evaluating] right now.”
One situation where formulation may prove useful is pulmonary delivery of siRNAs, and Lieberman said that her lab has begun preparations to collaborate with Baxter on this. This project, however, is “still on the drawing board,” she stressed.
Lieberman declined to comment on the specifics of her lab’s arrangement with Baxter, but indicated that the company appears interested in commercializing RNAi-based treatments, including one for herpes.
Still, “it’s always hard to know what [an industry partner’s] level of interest is,” she added.
Officials from Baxter declined to be interviewed for this article. In an e-mail to RNAi News, Jon Cammack, Baxter International’s vice president of technology resources, would only say that “the Promaxx microsphere RNAi program is early-stage research and part of broader, ongoing exploratory sciences within Baxter.
“As a scientifically driven organization, we are excited about the prospect of this innovative form of therapeutic delivery,” he added. “We look forward to collaborative and continued research on this and other exploratory initiatives over the next few years."
Baxter picked up the Promaxx technology in late 2002 when it acquired Epic Therapeutics. In a statement announcing the transaction, Baxter said the technology can enable “the creation of uniform microspheres that can be tailored to formulate many types of drugs, including protein drugs.
“The microspheres release the drugs in the body over a period of time from hours to weeks, thereby reducing the need for frequent injections,” the company said at the time. “In addition, the microspheres have potential application for efficient drug delivery to the lungs.”
Lieberman noted that a key aspect of the technology for RNAi applications is the level of drug concentration within the microspheres. In the study presented at the OTS meeting, the siRNA per microsphere was in the range of 70 percent to 80 percent.
Other than the RNAi payload, “there is very little else in them, which is pretty amazing,” she said.
Last year, Baxter presented data from a phase I study demonstrating that pulmonary insulin produced with the Promaxx technology and can be administered via a standard dry-powder inhaler to the deep lung.
Earlier this year, the company and collaborators from the University of Pittsburgh School of Medicine published data showing in a mouse model that Promaxx microspheres carrying antisense oligos against CD40, CD80, and CD86 could prevent type I diabetes and “exhibited a capacity to reverse clinical hyperglycemia, suggesting reversal of new-onset disease.”
“They had very good results with delivering antisense, so the question was whether the same technology could be used to deliver siRNAs,” Lieberman said.