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Alnylam Announces Progress in Pre-Clinical Hypercholesterolemia RNAi Therapeutic and microRNA Programs

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Alnylam Pharmaceuticals has announced that it presented pre-clinical data at the 2nd Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) held October 19-21, 2006 in New York City.

Alnylam scientists presented pre-clinical in vivo efficacy data from its hypercholesterolemia program evaluating new approaches for reducing LDL-cholesterol levels using RNAi therapeutics directed to a disease target called proprotein convertase subtilisn/kexin type 9, or PCSK9.

Alnylam is conducting this program in collaboration with researchers at University of Texas Southwestern Medical Center at Dallas with a focus on developing RNAi therapeutics for PCSK9, a key gene involved in the regulation of LDL cholesterol. An update on Alnylam’s microRNA (miRNA) effort was also presented at the meeting.
Data presented at the OTS meeting showed for the first time that small interfering RNAs (siRNAs), the molecules that mediate RNAi, can silence the PCSK9 gene in mice as measured by reductions in messenger RNA (mRNA) levels.

Further, gene silencing of the PCSK9 mRNA resulted in meaningful reductions in cholesterol levels, yielding the first in vivo evidence that pharmacologic targeting of PCSK9 can result in potential therapeutic benefit.

The in vivo efficacy data for PCSK9 was obtained using systemic RNAi delivery technologies such as those described by Alnylam earlier this year in primate studies (Nature 441: 111-114, 2006) where systemic RNAi targeting apolipoprotein B (apoB), another protein involved in cholesterol metabolism, resulted in reduced levels of apoB mRNA and protein, and significant lowering of LDL cholesterol.

“We are very encouraged that within months of the initiation of our program, we have obtained data demonstrating that systemic RNAi targeting PCSK9 showed in vivo efficacy in animal models,” said Victor Kotelianski, M.D., Ph.D., Vice President, Research at Alnylam.

“PCSK9 is a compelling target for the novel treatment of hypercholesterolemia where there is substantial clinical validation from human genetics, and where a systemically delivered RNAi therapeutic represents an exciting approach for disease intervention.”

In addition, Dr. Markus Stoffel, Professor at The Rockefeller University and Alnylam collaborator and Scientific Advisory Board member, presented an update on antagomirs, an RNAi therapeutic strategy to silence microRNAs (miRNAs.) miRNAs are a recently discovered category of genes that encode small RNAs that in turn regulate a larger number of genes in the human genome through the RNAi pathway.

Abnormal expression or mutation of miRNAs has been implicated in disease processes including cancer, viral infection, and metabolic disease.

Antagomirs are a potential new class of chemically modified RNA-based drugs that specifically silence miRNAs following therapeutically relevant administration in animals, and their discovery was first reported by scientists at Alnylam and The Rockefeller University in the journal Nature (Nature 438: 685-689, 2005). The company believes that this research creates the opportunity to design antagomirs that target miRNAs in the context of human diseases.

The data presented from the miRNA program builds on previous studies showing that intravenous administration of antagomirs resulted in profound reduction of corresponding miRNA expression in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries, and adrenals.

New findings demonstrated that direct administration of antagomirs to the central nervous system resulted in silencing of miRNAs expressed in the brain.

In addition, the key structural features of antagomirs and their mechanism of action was further explored, showing that antagomirs as short as 19 nucleotides in length maintain a high degree of selectivity and that antagomirs can mediate enzymatic degradation of the targeted miRNA.

“Antagomirs have the potential to be a new RNAi therapeutic approach to regulate miRNAs in vivo, possibly representing a novel strategy for silencing miRNAs involved in the cause or pathway of human disease,” said Muthiah Manoharan, Ph.D., Vice President, Drug Discovery at Alnylam.

“We continue to make important advances with our antagomir platform, which we view as an important component of our leading capabilities for discovery and development of innovative medicines that harness the RNAi pathway.”

Alnylam and The Rockefeller University have a collaboration agreement for research in the field of RNAi. Alnylam has taken an exclusive license to all of The Rockefeller University’s interest in antagomir technology.