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Intradigm Moves RNAi Drug Forward in Ocular Angiogenesis, Prepares to Publish

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Intradigm’s work with an intravenous RNAi-based treatment for ocular neovascularization diseases has been advancing steadily since CEO John Spears publicly disclosed the company’s interest in the area in late February (see RNAi News, 2/27/2004). The company just received a phase I SBIR grant to study its lead siRNA drug candidate in a mouse model of stromal keratitis, and is in the final stages of preparing to publish data detailing preliminary work in this area, RNAi News has learned.

The drug, called ICS-283, targets the vascular endothelial growth factor pathway and localizes in tissue by binding to integrin, according to Intradigm. While the company continues to see oncology as the first disease area in which it will develop ICS-283, it has also been working for almost a year with Barry Rouse, a professor of microbiology at the University of Tennessee, to evaluate the ability of the agent to inhibit ocular neovascularization in mouse models of SK, Intradigm CSO Martin Woodle told RNAi News.

According to Intradigm, the lesions of SK can result from repeated ocular infection by herpes simplex virus, which stimulates VEGF and causes neovascularization in the cornea. Rouse, who has worked for many years studying SK, has developed mouse models of the disease wherein VEGF over-expression is stimulated by purified HSV DNA or by synthetic CpG-motif oligonucleotides.

Although these models are most relevant to SK, Woodle said, they also relate to a variety of conditions associated with ocular angiogenesis. As such, Intradigm has been working with Rouse to evaluate ICS-283’s potential as a treatment, delivered either intravenously or topically, for ocular disease such as age-related macular degeneration, diabetic retinopathy, and SK.

“Although [ICS-283] looks very attractive to take forward in cancer first, there’re opportunities to look at it in other angiogenesis diseases such as [those] in the ocular area,” Woodle said. “We’re just looking to investigate other indications with that same drug.”

Rouse said that he and Intradigm researchers used siRNAs to inhibit VEGF, as well as “a couple of receptors”, in these mouse models. “The long and the short of it is that the siRNA approach, when either given systemically … or topically … has [yielded] some significant results,” he said. He added, however, that the topical delivery didn’t appear to work very well, probably due to the eye’s natural habit of washing away foreign matter.

These data, Rouse added, have just been accepted in principle for publication in the American Journal of Pathology.

Despite the “significant results”, Rouse said that he’s “a bit disappointed with the efficacy of siRNA, at least in the way we’ve used it in vivo. The difficulty is targeting all the producers and responders with the siRNA,” he said. “Even in vitro, it’s tough to transfect all the cells.”

In a bid to capitalize on the positive data, and overcome efficacy difficulties, Intradigm is now beginning a new project to study ICS-283 in Rouse’s mouse models, and is doing so with the help of the SBIR grant, worth $99,200, awarded by the National Eye Institute.

According to the grant’s abstract, the project will involve the selection of the “best siRNA duplexes for knockdown of mVEGF and mVEGF [receptor 1 and receptor 2] in vitro.”

Following this selection phase, local administration of these siRNAs in murine eye tissues with reporter genes will be optimized, and siRNA-mediated knock down of mVEGF and mVEGFR1 and mVEGFR2 will be achieved in mice eyes, the abstract states. Finally, the one-year project aims to reverse the ocular neovascularization process caused by HSV infection with siRNA-mediated antiangiogenesis.

“The completion of these objectives will lead to a phase II study with[in] a preclinical setting for … novel therapeutics to cure hepatic SK and other angiogenic eye diseases,” the abstract states.

Woodle said that the SBIR project would focus on intravenous delivery of ICS-283, a delivery approach expected to be more acceptable to the patient population than intraocular injection — “In fact, for wet AMD, the target cells are the ones lining the insides of the blood vessels, so it may be easier to get to the right place from an intravenous administration than from a local administration,” he added.

— DM

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