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Posted: August 9, 2010
Alnylam Scientists and Collaborators Report Significant New Advances in RNAi Delivery
(Nanowerk News) Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, and collaborators from the Massachusetts Institute of Technology (MIT), The University of British Columbia (UBC), AlCana Technologies, Inc., and Tekmira Pharmaceuticals Corporation, presented results from multiple ongoing research efforts regarding the discovery of novel technologies for the systemic delivery of RNAi therapeutics. A total of 12 oral presentations and posters were presented at the International Liposome Research Days and Lipids, Liposomes & Membrane Biophysics meeting held at UBC in Vancouver, Canada, August 4-8, 2010. Among many new research achievements, Alnylam scientists described the discovery of a new lipid called "MC3" that has been formulated with siRNAs into novel lipid nanoparticles (LNPs) that achieve effective in vivo gene silencing activity at single-digit microgram per kilogram dose levels.
"As is evidenced by the numerous high-quality presentations at this leading scientific meeting on liposome research, we and our collaborators continue to make very significant progress in advancing the discovery of novel and improved technologies for the systemic delivery of RNAi therapeutics. The breadth of presentations from Alnylam scientists and external research collaborators at MIT, AlCana, and UBC, together with our partnership and manufacturing agreement with Tekmira, exemplify the strength of Alnylam's leadership in RNAi delivery," said Kevin Fitzgerald, Ph.D., Senior Director, Research at Alnylam. "A key highlight emerging from this meeting is the discovery of our novel 'MC3' family of lipids and their superior performance in vivo when formulated into LNPs. Indeed, these formulations achieve effective gene silencing with single-digit microgram per kilogram dose levels, a result that sets a completely new industry benchmark for RNAi delivery."
Several oral presentations were made at the meeting describing scientific progress on the mechanistic understanding and potency improvements with LNP-based delivery of RNAi therapeutics. In particular, the discovery of a new lipid called MC3 was detailed; when formulated with siRNAs, MC3-containing ionizable LNPs (iLNPs) exhibited in vivo gene silencing potencies with ED50 levels in the single-digit microgram per kilogram range. As with other iLNPs, MC3-based LNP formulations achieved in vivo gene silencing activity in an apolipoprotein E (ApoE)-dependent manner. Further, presentations included an update on the applications of "C12-200" lipidoid-based cationic LNP (cLNP) formulations that achieve highly potent in vivo gene silencing efficacy in a non-ApoE-dependent manner. Additional findings related to the rational design of novel cationic and ionizable lipids that demonstrate improved properties for systemic delivery of RNAi therapeutics were also reported. Finally, results were presented related to the translation of LNPs into clinical development, including Alnylam's ALN-VSP and ALN-TTR programs developed in collaboration with Tekmira, which utilize an LNP formulation referred to as stable nucleic acid lipid particle (SNALP). In particular, real-time stability studies showed the ability of achieving stable formulations for at least two years at 2oC to 8oC storage conditions.
Oral presentations given at the meeting included the following:
"Progress on LNP-Mediated Delivery of RNAi Therapeutics," by Martin Maier, Ph.D., Senior Director, Drug Discovery at Alnylam;
"Progress in the Development of LNP Delivery Systems for siRNA: Advancing LNPs to the Clinic," by Mark Tracy, Ph.D., Senior Director, Pharmaceutical Operations at Alnylam;
"Combinatorial Development of Biomaterials and Synthetic siRNA Delivery Systems," by Professor Daniel Anderson, Ph.D., Department of Chemical Engineering, Harvard-MIT Division of Health Sciences & Technology, David H. Koch Institute for Integrative Cancer Research;
"Lipid Nanoparticle Delivery Systems for the Systemic Delivery of siRNA," by Pieter Cullis, Ph.D., Professor Biochemistry and Molecular Biology at UBC; and,
"Rational Design of Cationic Lipids for siRNA Delivery: Identifying Critical Structure/Activity Relationships," by Michael Hope, Ph.D., Chief Scientific Officer of AlCana.
In addition, multiple posters were presented at the meeting providing further updates on the systemic delivery of RNAi therapeutics. Specifically, data were presented describing the discovery of additional novel lipids; the use of small molecules in both cis and trans configurations to enhance LNP-based delivery; targeting-based approaches with LNPs; and, the achievement of extra-hepatic delivery of siRNAs, including to immune cells and prostate cancer tumor xenografts, with LNPs.
Posters presented at the meeting included the following:
"Development of Targeted LNPs for the Delivery of RNAi Therapeutics," Soma De, Ph.D., Scientist at Alnylam;
"Synthesis and Evaluation of Bicyclic Ketal-based Cationic Lipids for the Delivery of siRNA via Lipid Nanoparticle Systems," by Muthusamy Jayaraman, Ph.D., Principal Scientist at Alnylam;
"Influence of Cationic Lipid Composition on Gene Silencing Properties of siRNA in Primary Antigen Presenting Cells," by Genc Basha, Research Associate at UBC;
"siRNA Knockdown of the Androgen Receptor using Liposomal Nanoparticles to Treat Advanced Prostate Cancer," by Justin B. Lee, Graduate Student at UBC;
"Reverse Headgroup Lipids: A New Class of Lipids With Enhanced Bilayer Destabilizing Characteristics," by Alex Leung, Graduate Student at UBC;
"Identification of Small Molecules that Enhance Intracellular Delivery and Function of siRNA Presented in LN in vitro," by Paulo Lin, Postdoctoral Fellow at UBC; and
"Identification of Small Molecules that Enhance Uptake of Liposomal Nanoparticles in Target Cells," by Chris Tam, Research Associate at UBC.
"The significant progress we are making in the delivery of RNAi therapeutics is certainly clear as demonstrated by the presentations and posters from Alnylam and collaboration scientists," said Laurence Reid, Ph.D., Senior Vice President and Chief Business Officer at Alnylam. "Importantly, Alnylam's exclusive relationships with key research efforts at MIT, UBC, and AlCana enable discovery of new delivery technologies – including intellectual property and know-how – that expand our overall RNAi therapeutics platform. Of course, advances in our RNAi platform strengthen the value we deliver to our existing partners and also form the foundation for Alnylam's future partnerships."
About RNA Interference (RNAi)
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. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics for the treatment of a wide range of disease areas, including respiratory syncytial virus (RSV), liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington's disease. In addition, Alnylam formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in manufacturing processes for biotherapeutic products, including recombinant proteins and monoclonal antibodies. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are joint owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.