Alnylam Publishes Pre-Clinical Research on Direct CNS Delivery of RNAi Therapeutics

Alnylam Pharmaceuticals, Inc. has announced that it has published data in the journal Oligonucleotides demonstrating robust silencing of an endogenous oligodendrocyte gene with small interfering RNAs (siRNAs), the molecules that mediate RNAi, when administered by direct delivery to the central nervous system (CNS) in both rats and non-human primates.

"These data extend the successful delivery of siRNAs in vivo to an important additional cell type within the CNS," said Dinah Sah, Ph.D., Vice President, Research, CNS, and Oncology of Alnylam.

"While previous studies have shown successful CNS delivery of siRNAs in neurons, this published study shows robust RNAi silencing of oligodendrocyte-specific genes. These findings suggest potential therapeutic applications for RNAi therapeutics in certain diseases demonstrating oligodendrocyte pathology such as progressive multifocal leukoencephalopathy (PML), multiple sclerosis, and cerebral palsy," said Sah.

"This paper is a yet another proof point of our continued commitment to scientific excellence and also another example of Alnylam's scientific leadership in the RNAi therapeutics field," said Jack Schmidt, M.D., Chief Scientific Officer of Alnylam. "Indeed, this is the fourteenth paper Alnylam has published in 2008, well exceeding our goal of ten or more scientific papers published in peer-reviewed journals this year."

The research conducted by Alnylam scientists, some of which was presented at the Keystone RNAi meeting earlier this year, demonstrated that in vivo silencing of an endogenous oligodendrocyte-specific gene by an RNAi therapeutic was dose dependent, durable, and mediated by an RNAi mechanism. Specifically, the data showed that:

• siRNAs administered in a rodent model achieved successful delivery and silencing of an endogenous oligodendrocyte gene target (2',3'-cyclic nucleotide 3'-phosphodiesterase or "CNPase") in a specific manner as compared with a control siRNA;

• direct CNS delivery of siRNA in the rodent model silenced the CNPase mRNA by approximately 75 percent, as compared with a control siRNA, and was durable for up to one week;

• increasing the infusion rate increased the distribution of CNPase mRNA suppression in white matter regions distant from the infusion site;

CNPase silencing was mediated by an RNAi mechanism as measured by 5'RACE; and, direct infusion of an siRNA into the CNS in a non-human primate model resulted in silencing of the CNPase mRNA by 55 percent.