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Quark Data Shows AMD Drug Reaches Target Cells, Avoids Immune Response

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Quark Pharmaceuticals last week unveiled preclinical data demonstrating that its siRNA-based wet age-related macular degeneration and diabetic macular edema therapy, dubbed PF-4523655 and currently under phase II development by partner Pfizer, does not stimulate an immune response that has been associated with similar drugs.

According to the data, which were presented at the annual meeting of the American Association for Research in Vision and Ophthalmology, the drug is able to enter target cells in the eye and inhibit its target gene, but doesn't activate toll-like receptor 3.

The results of the study are noteworthy because the issue of immune stimulation, especially involving TLR3, has become an increasingly troublesome one for the RNAi field lately following the publication of a number of reports describing the unintended triggering of these effects with siRNAs.

Most prominent among these is a paper by a team from the University of Kentucky led by Jayakrishna Ambati that showed any siRNA at least 21 nucleotides in length, regardless of its target or sequence, activated TLR3, which in turn suppressed angiogenesis in the retinas of a mouse in which a laser injury triggered choroidal neovascularization.

Among those siRNAs evaluated by Ambati and his colleagues were two being studied in the clinic as treatments for AMD: bevasiranib, which targets vascular endothelial growth factor and is being developed by Opko Health, and AGN211745 (formerly Sirna-027), which targets VEGF receptor-1 and was licensed by Allergan from Sirna Therapeutics (see RNAi News, 6/28/2007 and 10/7/2005). The siRNAs in both of these drugs are unmodified.

Ambati followed up his initial findings earlier this year with a report indicating that all siRNAs inhibit both hemangiogenesis and lymphangiogenesis as a result of TLR3 activation (see RNAi News, 4/9/2009).

Notably, earlier this year Opko announced that it had halted phase III development of bevasiranib after preliminary data showed the drug was "unlikely" to meet its primary endpoint (see RNAi News, 3/12/2009).

In collaboration with Ambati, who is a member of Quark's medical advisory board, company researchers set out to demonstrate that PF-4523655, a 19 nucleotide-long, 2'-O-methyl-modified siRNA that targets RTP-801, "enters its target cells in the back of the eye and does not activate [the] TLR3 receptor," according to an abstract from Quark's ARVO presentation.

To do so, intravitreal injections of either fluorescent or non-labeled PF-4523655 were administered to mice. The fluorescent siRNAs were detected in retinal ganglion cells, the retinal pigment epithelium, and retinal and choroid endothelial cells, the abstract states.

In situ hybridization showed "guide strand-specific signal throughout the retina over numerous cell types with the most concentration" in retinal ganglion cells, while qPCR analysis demonstrated RTP-801 knockdown in eyes treated with the drug.

"Treatment of mouse or human TLR3 reporter cells with [1 nanomolar to 10 micromolar concentrations of PF-4523655], either naked or lipofectamine-formulated, did not elicit reporter activation," the abstract notes. Similar results were obtained in experiments with toll-like receptor 7 and toll-like receptor 9 reporter systems.

"We concluded that [PF-4523655], unlike some other siRNA molecules, enters target cells in the back of the eye and elicits its pharmacological effect via target gene knockdown and not via TLR3 activation," the researchers concluded in the abstract.

"We believe that the results presented at ARVO continue to substantiate … Quark's ability to develop highly specific siRNA products and advance them through the clinic toward commercialization," Quark President and CEO Daniel Zurr said in a statement today.

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