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Alnylam Publishes Preclinical Data on RNAi-based Cholesterol Treatment

NEW YORK (GenomeWeb News) – Alnylam Pharmaceuticals today announced that it has published pre-clinical data from its RNAi-based cholesterol treatment program.
In a paper appearing online last night in the Proceedings of the National Academy of Sciences, researchers from Alnylam, the University of Texas Southwestern Medical Center, Roche Kulmbach, and the Massachusetts Institute of Technology showed that they could specifically target the messenger RNA for PCSK9, a protein governing cholesterol homeostasis, in mice, rats, and non-human primates, using small interfering RNA.
The result: lower total blood cholesterol levels in mice and rats and decreased low density lipoprotein cholesterol levels in non-human primates. Although there is a ways to go before the treatment can be tested in humans, those involved say the siRNA-based gene silencing may eventually augment or even replace existing cholesterol treatments
“It’s certainly a very direct approach,” said co-senior author Jay Horton, a molecular geneticist at the University of Texas Southwestern Medical Center and an Alnylam consultant. “It certainly holds a lot of promise.”
The putative treatment stems from genetic studies showing that loss-of-function mutations or deletions in the gene coding for proprotein convertase subtilisin/kexin type 9 — or PCSK9 — can decrease low density cholesterol (LDL) levels and cardiovascular heart disease risk.
PCSK9 regulates the level and function of the low density lipoprotein receptor (LDLR). When PCSK9 is repressed, LDLR levels increase and blood cholesterol levels decline. On the other hand, when the protein is over-expressed, LDLR levels plummet, increasing the amount of cholesterol circulating in the blood.
To determine whether they could lower LDL cholesterol levels by silencing PCSK9 mRNA, the researchers first generated 150 different PCSK9- targeting siRNAs. The current paper focuses on the four most active of these, Horton explained. All four compounds seemed to have comparable activity, although some appeared to be slightly more effective in certain animal models, he added.
The siRNAs were delivered to cells using a lipidoid nanoparticle method developed by Alnylam in collaboration with researchers at MIT. The short RNA molecules were loaded into liposomes or lipid disks and then administered via tail injections in rodents or intravenous infusions in cynomolgus monkeys. The compounds appear to function predominantly in the animals’ livers.
As anticipated, the siRNAs appear to selectively silence PCSK9 mRNA in each of the animal models tested (although PCSK9 mRNA in monkey livers was not measured directly).
In mice and rats, siRNA treatments cut the levels of PCSK9 mRNA in the liver by more than half. That was associated with a roughly 30 percent decrease in total plasma cholesterol concentration in mice and a 50 percent to 60 percent decrease in total serum cholesterol in rats. Liver triglycerides and cholesterol levels, on the other hand, did not change significantly, although the level of LDL receptors increased up to five-fold.
Similarly, in mice expressing human PCSK9, the siRNAs silenced more than 70 percent of the human PCSK9 mRNA and dramatically decreased the amount of the human PCSK9 protein circulating in the blood.
Next, the researchers tested the siRNAs in four cynomolgus monkeys, measuring plasma levels of PCSK9, LDL, high density lipoprotein, triglycerides, and total cholesterol. They saw that — on average — LDL cholesterol levels decreased by more than half in the treated monkeys, with one of the four exhibiting an almost 70 percent decrease in LDL cholesterol. These levels returned to baseline after two to three weeks.
At the moment, the effects of the siRNA-based treatment appear to be comparable to those seen with existing cholesterol drugs, Horton noted. But, he added, some hypercholesterolemia patients do not achieve sufficient decreases in LDL cholesterol on these drugs alone. Once the duration of action, mode of delivery, and safety have been validated in humans, the siRNA-based treatment could eventually complement such treatments, he said.
“I think that the reason this particular target is so attractive is because of the human genetic data,” Horton said. Because individuals with PCSK9 loss-of-function mutations appear to be healthy, he added, “It’s very likely [PCSK9] is going to be safe from a target standpoint.”
Alnylam is currently working toward developing the RNAi-based cholesterol treatment, called ALN-PCS, although its liver cancer drug, ALN-VSP, is currently at the forefront of drug development plans. The company is hoping to submit an investigational new drug filing for ALN-VSP this year, according to statements made by Alnylam CEO John Maraganore during Alnylam’s second-quarter conference call yesterday. He noted that both the cholesterol and liver cancer programs are progressing “very actively.”
During the call, Alnylam Vice President of clinical research Akshay Vaishnaw said that ALN-PCS cholesterol treatment “continues to advance in preclinical studies toward a potential IND in 2009.”

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