Alnylam Pharmaceuticals, Inc, a leading RNAi therapeutics company, and collaborators from the David H Koch Institute for Integrative Research at the Massachusetts Institute of Technology (MIT) announced the publication of new data in the journal Proceedings of the National Academy of Sciences (PNAS) describing further advancements in discovery and development of novel 'lipidoid' formulations for the systemic delivery of RNAi therapeutics. Lipidoids are lipid-like materials discovered for the delivery of RNAi therapeutics, and were originally described by Alnylam and MIT collaborators (Akinc et al., Nature Biotechnology, 26: 561-569, 2008). In particular, the new research findings demonstrate the discovery of new lipidoid materials that facilitate significantly improved in vivo potency for RNAi therapeutics.

"We are very encouraged with the substantial progress we and our collaborators have made with lipid nanoparticles (LNPs) based on novel lipid-like materials such as lipidoids," said Victor Kotelianski, senior vice president, Distinguished Alnylam Fellow. "To our knowledge, these new LNP formulations facilitate endogenous liver gene silencing at doses that are orders-of-magnitude lower than those required by previously described siRNA delivery approaches, thereby setting a new standard in potency for the systemic delivery of RNAi therapeutics. In addition, the current study is the first to report on the simultaneous and highly specific RNAi-mediated silencing of as many as five liver targets in vivo, serving as proof of principle that multiple genes involved in similar or divergent biological pathways can be silenced with a single administration of a single drug product. From a therapeutic standpoint, this could enable novel pharmaceutical strategies, where silencing of multiple targets could achieve an enhanced level of efficacy."

The new pre-clinical data describe a formulation based on a lipidoid known as 'C12-200' that was shown to enable gene silencing in vivo in rodents at doses below 0.01 mg/kg; demonstrate complete, rapid, and durable gene silencing in rodents as soon as 24 hours with protein levels returning to baseline within 20 to 35 days; specifically inhibit expression of as many as five target genes simultaneously after a single injection of an LNP formulation in rodents; and, demonstrate potent and selective silencing of the clinically relevant gene transthyretin (TTR) at doses as low as 0.03 mg/kg in non-human primates.

"We are excited by the delivery performance of these new formulations," said Daniel Anderson, of the David H Koch Institute for Integrative Cancer Research at MIT. "This work demonstrates that doses measured in micrograms per kilogram can provide potent gene silencing with RNAi in several species including primates. This greatly improved efficacy allows us to dramatically decrease the dose levels of LNPs, thereby widening the therapeutic index, and also opens the door to formulations that can simultaneously inhibit multiple genes or pathways."

Lipidoid formulations represent one of several approaches Alnylam is pursuing for systemic delivery of RNAi therapeutics. Additional approaches include other lipid nanoparticles formulations, mimetic lipoprotein particles (MLPs), siRNA conjugation strategies, and single-stranded RNAi, among others. Alnylam is currently enrolling patients in a Phase I clinical program with its systemic RNAi therapeutic ALN-VSP for the treatment of liver cancers. In addition, Alnylam intends to initiate a phase-I trial in the first half of 2010 for an additional systemic RNAi therapeutic, ALN-TTR for the treatment of TTR-mediated amyloidosis. ALN-VSP and ALN-TTR both utilize a first generation lipid nanoparticle formulation known as stable nucleic acid-lipid particles (SNALP), developed in collaboration with Tekmira Pharmaceuticals Corp.

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development.

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi.

The MIT Center for Cancer Research (CCR) has changed its name to the David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute - pronounced 'coke') effective March 2008.