Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it presented new data related to its overall delivery research efforts including the rational design of Mimetic Lipoprotein Particles, or MLPs, a novel technology for the systemic delivery of small interfering RNAs, or siRNAs, the molecules that mediate RNAi. In addition, Alnylam scientists and collaborators presented additional new data on systemic delivery and provided an update on RNA activation (RNAa) technology. These new data were presented at the 5th Oligonucleotide Therapeutics Society/19th Antisense Joint Symposium held November 3-6, 2009 in Fukuoka, Japan.
“Delivery of siRNAs remains one of the most important objectives in our efforts to advance RNAi therapeutics to patients,” said Victor Kotelianski, M.D., Ph.D., D.Sc., Senior Vice President, Distinguished Alnylam Fellow. “Accordingly, we are very excited by our new efforts in the rational design of MLPs, a whole new strategy for systemic delivery. Indeed, MLPs are designed to harness natural physiologic pathways in their delivery of siRNAs and they represent an important convergence of Alnylam’s research on conjugate- and lipid nanoparticle-based delivery strategies. In addition to our continued efforts on a wide range of other delivery technologies, this new line of research continues to demonstrate Alnylam’s scientific leadership in RNAi.”
In a poster titled “Lipophilic siRNA Delivery by Reconstituted Lipoprotein Particles In Vivo” Tomoko Nakayama, Ph.D., Associate Director, Research at Alnylam, presented for the first time the rational design and characterization of MLPs as an RNAi delivery platform. MLPs were designed to mimic the physiologic properties of endogenous lipoprotein particles and were engineered using recombinant human apolipoprotein A1 (rh-apoA1) or recombinant human apolipoprotein E (rh-apoE), phosphatidylcholine, and a cholesterol-conjugated siRNA (chol-siRNA). The resulting MLPs had biophysical properties comparable to normal high-density lipoprotein (HDL, or “good” cholesterol) particles including a mean diameter size of approximately 10 nm. The stoichiometry for siRNA:particle loading ratio was observed to be 1:1. The reported in vivo studies were performed in mice using MLPs with chol-siRNAs targeting apolipoprotein B (apoB), the major apolipoprotein involved in the metabolism of low-density lipoprotein (LDL, or “bad”) cholesterol. Administration of the MLP resulted in silencing of the apoB mRNA by up to 80% with an associated 50 to 80% reduction in levels of plasma apoB protein and cholesterol in mice. These data also demonstrated significant improvements in the potency of apoB silencing when using MLP-delivery of siRNAs as compared with use of chol-siRNAs alone. The study further demonstrated that apoE-MLP was more effective in delivering siRNAs than apoA-MLPs, at least as measured for the silencing of the liver-expressed target gene.
In addition, Dr. Muthiah Manoharan, Alnylam’s Vice President, Drug Discovery, gave a talk titled “Chemical Strategies for Delivering RNAi” in which he presented new research on lipid nanoparticle and conjugate-based delivery of siRNA. The new data showed continued improvement in the in vivo potency of siRNA delivered by lipid nanoparticles (LNPs), where the median effective dose (ED50) for gene silencing was achieved at microgram/kilogram dose levels. Further, quantitation of siRNA revealed the ability to achieve ED50 target gene silencing at tissue levels of approximately one nanogram/gram tissue.
“The resulting research efforts of our scientists and collaborators continue to represent what we believe is remarkable progress on delivery of RNAi therapeutics,” said Dr. Manoharan. “Importantly, with the novel LNP formulations we have discovered, we are now on a research trajectory for in vivo gene silencing potency of siRNA at single-digit microgram/kilogram dose levels. Further, we have now documented for the first time that the siRNA tissue levels required for gene silencing are approximately one nanogram/gram tissue, highlighting the power of harnessing a natural, catalytic mechanism.”