Lipid Nanoparticles Delivery
Successful delivery of the payload is a key aspect for the successful use of RNAi therapeutics. Tekmira Pharmaceuticals utilizes lipid nanoparticles (LNPs) as a delivery technology platform. The uniformly constructed LNPs encapsulate their target-specific double-stranded siRNA molecules or other nucleic acids.
“Nucleic acids are relatively large in size and unstable in the blood compartment,” explained Ian MacLachlan, Ph.D., evp and CSO. “They do not readily diffuse across the membranes of target cells, and thus need an effective delivery vehicle.
“Our LNP technology protects the nucleic acid payload and allows us to control the circulation time in blood. Since it is a modular platform technology, there are literally thousands of lipid combinations and lipid or lipid:nucleic acid ratios that can be customized for specific delivery applications."
According to Dr. MacLachlan, the field is tackling these challenges and making headway.
“As we continue developing formulations that are increasingly clinically validated for increased potency and reduced toxicity, we are acquiring new understandings of how to improve the therapeutic index of these drugs.
“Recent research has provided important information about the structural basis for the chemical toxicities associated with high doses of lipid excipients and the nucleic acids themselves. Further, we are beginning to unravel how immune toxicities can manifest through unwanted engagement of either the innate or adaptive immune systems, and how these can be avoided.”
Tekmira’s LNP siRNA delivery platform (known as SNALP) has confirmed RNAi-mediated efficacy in several preclinical models including oncology and infectious and metabolic diseases. Aside from systemic delivery, the company also has made progress in nebulization-mediated delivery of siRNA into the respiratory tract.
“One recent example of progress is that we have received approval from the FDA to initiate Phase I clinical trials with our Ebola therapeutic, TKM-Ebola. This disease and those caused by other hemorrhagic fever viruses have no approved treatments.
“Our preclinical studies demonstrated that the Ebola therapeutic provided 100% protection from an otherwise fatal infection with Zaire Ebola virus in nonhuman primates.”
Dr. MacLachlan said he is pleased with how the field is progressing. “This is an incredibly exciting time. Tekmira expects that six or seven of our and partner Alnylam’s LNP-based products will have entered the clinic by the end of 2012. A few years ago, we would have said that we couldn’t be sure if RNAi would ever translate into therapeutics. But now, especially with the use of siRNAs, we are close to achieving that goal.
“The last few years have seen us improve our understanding on a number of fronts such as development of more potent siRNA and lipid chemistries, advantageous sequence design, and controlling responses of the immune system. At the same time we are seeing the LNP approach validated in the clinic. All of this has increased my confidence that RNAi therapeutics are on the horizon.”