In contrast to miRNAs, siRNAs are usually perfectly complementary to their targets. They are thus very effective at eliminating gene expression. For this reason, synthetic siRNAs have been generated for a number of therapeutic uses. But of course, there are hurdles: stability, potency, off-target effects, and efficient delivery of synthetic siRNAs are some of the major challenges for successful application of this technology in the clinic.
Quark Pharmaceuticals is committed exclusively to developing siRNA drugs. One of its siRNAs has finished Phase II trials for the treatment of wet age-related macular degeneration and diabetic macular edema.
This siRNA was licensed to Pfizer, which conducted the trials. The diabetic macular edema trial was reportedly the first siRNA Phase II trial to show dose-dependent efficacy—there was an actual and significant improvement in clinical endpoint (visual acuity), not just a knockdown of gene expression.
Elena Feinstein, M.D., Ph.D., Quark’s CSO, spoke about some exciting results with another of the firm’s therapeutic siRNAs, this one to treat nonarteritic ischemic optic neuropathy, at Keystone Symposium’s recent “Nucleic Acid Therapeutics” conference. She characterized these results as “fresh from the oven.”
Both siRNAs treat eye diseases; Dr. Feinstein said that they decided to start there because there was no delivery problem. Quark uses a chemical modification of its siRNAs to render them highly specific and stable to nucleases, and to prevent their generating an immune response.
“These modifications are suitable for eye use. You can’t inject liposomes or viruses into the eye—it will cause inflammation,” said Dr. Feinstein. “But ours can be used for other local administration.”
The new results she presented show that when given their new siRNA, “these patients did not deteriorate further. From the moment they received the injection, visual loss was halted in all 20 patients. In fact, all of them gained vision that lasted over the three months of analysis.”
Dr. Feinstein noted that this was a Phase I trial to assess safety, and that there were no placebos, since that would involve an injection into the eye that no one was particularly keen to undergo needlessly. But even so, she was excited because historical data in the same type of patients shows further deterioration of visual acuity occurring over time in many of them.