Naked siRNA Delivery
Delivery of siRNA is not a major hurdle for every organ and tissue, noted Elena Feinstein, M.D., Ph.D., CSO at Quark Pharmaceuticals. “We decided to examine which cells and tissues were amenable to efficient delivery of naked (i.e., substantially nonformulated) siRNA and then looked for diseases involving these cells.”
Just as important to choosing the optimal target and indication, the company also worked to develop a strategy for designing and then chemically stabilizing the siRNA. “We were able to stabilize and improve the drug properties of siRNA therapeutics by using specific chemical modifications.”
Dr. Feinstein cited the example of siRNA and certain kidney diseases. “After intravenous administration, Quark synthetic siRNAs are rapidly filtered by the kidney and then some of the siRNA is reabsorbed by the proximal tubules.”
Proximal tubules represent the kidney substructure that is specifically affected in the majority of diseases associated with acute kidney injury.
“This prompted us to focus on indications involving acute kidney injury and on systemic administration of naked siRNA as a delivery mode. We found that we can administer naked siRNA intravenously and readily see a therapeutic effect in rat models of ischemia-reperfusion injury in kidneys.”
The company’s QPI-1002 is the first systemic siRNA drug to enter clinical trials. It targets p53 mRNA and currently is in development for prevention of acute kidney injury after major cardiovascular surgery and for prophylaxis of delayed graft function in kidney transplant patients. Phase I/II trials are fully enrolled and are currently being completed. The plan is to start Phase II studies later this year.
“There are other target tissues that are also suitable for naked siRNA therapies such as the eye, where many cell types can efficiently take in chemically modified siRNA, but in particular retinal ganglion cells,” according to Dr. Feinstein. “We have developed an siRNA that can be directly injected into the eye as an ocular neuroprotective agent. The initial clinical trials will focus on treating an acute ischemic disorder of the optic nerve called nonarteritic anterior ischemic optic neuropathy. Those studies are in Phase I trials. Our partner, Pfizer, is currently conducting two Phase II trials with PF-4523655, another siRNA developed by Quark, for diabetic macular edema and wet age-related macular degeneration.”
Overall, optimism remains high that the barriers to the successful delivery of siRNA will be overcome. The most positive signs for the future of siRNA-mediated gene silencing are emerging studies showing knockdown with low doses of siRNA in complexes or conjugates that target specific cell types.