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Jan 15, 2010 (Vol. 30, No. 2)

RNAi Moves One Step Closer to Clinic

Researchers Tout Delivery Strategies that Have the Potential to Get New Drugs into Trials Sooner

  • Liposomally Formulated siRNA

    Click Image To Enlarge +
    Fluorescently labeled liposomal siRNA (AtuPLEX) highlights the tumor vasculature after intravenous administration.

    Atu027, a liposomally formulated siRNA that targets protein kinase N3 (PKN3) expression in the vascular endothelium, is another RNAi therapeutic that will be discussed at the conference.

    “Atu027 targets the vasculature in the tumor; if the tumor gets no nutrition, it will not grow. It’s a novel approach to cancer research,” says Klaus Giese, Ph.D., CSO at Silence Therapeutics.

    “The PKN3 protein acts in the tumor vasculature and that made it an addressable target. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates resulted in specific, RNAi-mediated silencing of PKN3 expression.

    “We have shown the therapeutic efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph-node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density.”

    Creating a delivery method had its challenges, notes Dr. Giese. “We faced a typical dilemma in that the siRNA oligonucleotide itself was not an ideal drug molecule for intravenous administration. It is large, and highly charged and rapidly cleared from the body. But our liposomal formulation of the siRNAs enabled us to trigger RNAi in the endothelium in a safe and effective manner.

    “We have obtained new insight from Atu027 testing in additional tumor models supporting Atu027s antimetastatic activity.” Atu027 is currently being tested in a Phase I trial on subjects with advanced solid cancers.

  • LNA Antimirs

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    In untreated hepatocytes (top), miR-122s bind to seed region matches in the 5’ region of HCV. In treated hepatocytes (bottom), miR-122 hybridizes with SPC3649, and HCV binding sites are kept empty. (Santaris Pharma)

    Much attention has been paid to double-stranded RNAs in the last few years, and there is a growing consensus about the  challenges in the field, namely delivery and off-target effects, notes Henrik Ørum, Ph.D., vp and CSO at Santaris Pharma. “As with new technologies, those issues are not easily solved. We’ve had significant interest in our locked nucleic acid (LNA) single-stranded format, as there are no issues with delivery and off-target effects as those seen with double-stranded RNAs.”

    The LNA drug platform creates synthetically modified chemical versions of the normal nucleic acid building blocks of RNA. These modified chemical versions improve the drug-like qualities of resulting oligonucleotides by improving affinity to their target RNA, boosting resistance to metabolism, and improving tissue uptake. On systemic administration of these “naked” molecules, LNA-based therapeutics are delivered to their targets where they show efficacy as well as safety.

    The company’s work with drug candidate SPC3649 will be presented at the conference, it was also published in Science in December. Dr. Ørum notes that SPC3649 targets and inhibits the liver-specific microRNA-122, which is required for hepatitis C virus (HCV) replication.

    “Unlike many other therapies for HCV, SPC3649 works by targeting a host factor in the liver that the virus needs to replicate,” adds Dr. Ørum. “Targeting a host factor rather than attacking the virus directly has significant implications as it may reduce the risk of the virus becoming resistant to therapy, which remains a major concern for current therapies.”

    According to Dr. Ørum, SPC3649 provided continued efficacy in animals up to several months after the treatment period with no adverse events and no evidence of viral rebound or resistance. “The preclinical data show changes in the expression of key genes that may help patients who do not respond to interferon treatment to become responsive. This could be a real game-changer for the treatment of patients infected with HCV.”


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