First Demonstration of Therapeutic Gene Silencing in Primates with Systemic RNAi


Alnylam Pharmaceuticals, Inc. announced the first published demonstration in primates that a systemically delivered RNAi therapeutic can potently silence an endogenous disease-causing gene in a clinically relevant manner. Alnylam and its collaborators at Protiva Biotherapeutics, Inc., demonstrated silencing in primates of the gene for apolipoprotein B (apoB), a protein involved in cholesterol metabolism, with clinically significant efficacy as demonstrated by reductions in levels of cholesterol and low-density lipoproteins (LDL). According to Alnylam, this peer-reviewed research, published in Nature, represents a major advance because it suggests that an RNAi therapeutic can be effective when delivered systemically using a dosage appropriate for application in future human clinical studies.

In the published research, Alnylam scientists and collaborators demonstrated potent silencing in primates of the gene for apoB, a disease-causing protein which to date has not been amenable to targeting with traditional small molecule, protein, or antibody therapies. The achievement of this result by systemic administration through the bloodstream demonstrates the broad potential of RNAi therapeutics to target disease-causing genes, and significantly expands the previously demonstrated opportunity for RNAi therapeutics to treat human disease by direct administration to sites of disease, such as with respiratory or ocular delivery.

In the study Alnylam scientists and collaborators showed that systemic delivery in non-human primates of a chemically optimized small interfering RNA, or siRNA, can result in silencing of the apoB messenger RNA (mRNA), leading to significant reductions in blood levels of the apoB protein. These effects were proven to occur through an RNAi-mediated mechanism, and resulted in immediate, potent, and durable therapeutic efficacy. The siRNAs were formulated with liposomes that enable delivery to liver cells. The observed therapeutic effects included significant reductions in serum levels of cholesterol and LDL, which together represent the so-called "bad cholesterol" associated with development of atherosclerosis and coronary artery disease. Following administration of a single intravenous bolus dose at low dosages from 1.0-2.5 mg/kg, these reductions were observed as early as 24 hours after treatment and lasted for at least 11 days. A single siRNA injection resulted in dose-dependent silencing of apoB mRNA expression, with maximal silencing of over 90%. The silencing of apoB was proven to occur through an RNAi-mediated mechanism of action. In addition, plasma apoB levels were reduced by more than 75%, cholesterol levels by more than 60%, and LDL levels by more than 80%. In the study of 18 animals, the treatment was well tolerated with only transient liver enzyme elevation observed at the highest dose.

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