By Doug Macron
Santaris Pharma unveiled its newest microRNA therapeutic program this week having acquired intellectual property from Massachusetts General Hospital related to the use of miR-33 as a target for cardiovascular disorders including hypercholesterolemia.
In doing so, Santaris has expanded its stable of cardiovascular drug candidates based on its proprietary locked nucleic acid technology and added the second miRNA-inhibiting compound to its pipeline.
According to Santaris CSO Henrik Orum, the company specifically licensed from Mass General patent application WO2010120508, which was filed with the World Intellectual Property Organization about a year ago. Entitled “Regulation of miR-33 microRNAs in the Treatment of Cholesterol-Related Disorders,” the application claims compositions of nucleic acid sequences that target miR-33 and their use in treating cholesterol-related disorders.
Having already established itself in the miRNA therapeutics space with the advancement of the hepatitis C therapy miravirsen, an LNA that inhibits miR-122, into phase II testing (GSN 9/23/2010), Santaris is “continuously seeking to expand its portfolio of … new drugs in the miRNA space,” Orum told Gene Silencing News via e-mail.
“A key to fulfilling that ambition is our ability to access miRNA targets that satisfy our scientific and commercial target selection criteria,” he wrote. “Our assessment is that miR-33 is one such target.”
Data from the lab of Mass General researcher Anders Naar, the lead inventor on the in-licensed patent application, have shown that knocking down miR-33 “offers the opportunity to combat cardiovascular diseases by increasing plasma” high-density lipoprotein, Orum added. “We believe that a drug with this mode of action is an attractive and important addition to our overall metabolic franchise.”
That franchise currently includes two preclinical LNA-based agents designed to reduce low-density lipoprotein: SPC5001, which targets proprotein convertase subtilisin/kexin type 9, and SPC4955, which targets apolipoprotein B.
Key to Santaris' interest in the Mass General IP are data published in mid-2010 in Science showing that miR-33 can affect cholesterol hemeostasis by working with sterol regulatory element-binding proteins, which are key transcription regulators of cholesterol synthesis and uptake genes.
SREBP transcription factors are “critical regulators of cholesterol/lipid homeostasis, which act by controlling the expression of many cholesterogenic and lipogenic genes … [but it is] unclear how this regulatory circuit is coordinated with opposing pathways that mediate cholesterol/lipid efflux or degradation to achieve appropriate cholesterol/lipid levels to satisfy cellular and physiological demands,” Naar and colleagues reported in the paper.
With increasing awareness of the role of miRNAs as “important modulators of numerous cellular processes that affect organism growth, development, homeostasis, and disease,” the researchers noticed an “intriguing presence” of miR-33 within intronic sequences of the SREBP genes in organisms ranging from Drosophila to humans, and they set out to see whether it showed any functional association with SREBP host genes.
Their research revealed that miR-33a and miR-33b, the two isoforms of the miRNA that exist in humans, are “embedded within introns of the SREBP genes target the adenosine triphosphate–binding cassette transporter A1, an important regulator of high-density lipoprotein synthesis and reverse cholesterol transport, for post-transcriptional repression,” according to the paper.
Further investigation showed that antisense inhibition of miR-33 in mouse and human cell lines up-regulated ABCA1 expression and increased cholesterol efflux. Based on these in vitro results, they hypothesized that modulating ABCA1 levels by miR-33 inhibiting might lead to “augmented HDL cholesterol levels in a mammalian in vivo model,” the team wrote. Indeed, administration of LNAs against the miRNA in mice on a Western-type diet elevated plasma HDL levels compared with control mice.
“In these experiments, there was also no apparent hepatotoxicity … [and] the observed elevation in plasma HDL cholesterol in response to [LNA] treatment is consistent with regulation of ABCA1-dependent cholesterol efflux by miR-33a in vivo,” they added.
The data, the team concluded, “reveal that miR-33 exerts post-transcriptional control of the ABCA1 cholesterol transporter, with important consequences for cholesterol trafficking in vitro and HDL synthesis in vivo … [and further] point to the possibility of antisense therapeutic targeting of miR-33a/b as a strategy to increase HDL in individuals suffering from cardiometabolic diseases.”
Orum declined to comment on how advanced Santaris' miR-33 program is at this point, but said that the decision to license Mass General's IP “is obviously a strong sign that we believe the target is therapeutically relevant and that we are comfortable that our LNA platform can produce a drug candidate with attractive properties.”
He added that it is too early to provide a time line on when a miR-33-targeting drug might be ready for human testing, but said that Santaris is “typically able to move from program initiation to clinical trial in less than 18 months.”
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