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Jun 1, 2009 (Vol. 29, No. 11)

Delivery Approaches for RNAi-Based Drugs

Getting siRNA into the Right Place in the Cell Might Not Be a Problem for Much Longer

  • Liposomes: Alive and Well

    Click Image To Enlarge +
    Aptamer targeting of the HIV-1 envelope glycoprotein gp120
    (Beckman Research Institute)

    Although liposome-based delivery systems are fraught with cytotoxicity and liver-targeting effects, there are still innovative liposome-based delivery systems entering the field. Roger Adami, Ph.D., associate director of molecular pharmaceutics at MDRNA, will highlight new applications of the company’s  DiLA2 platform for liposome-based siRNA delivery at the conference.

    DiLA2 enables MDRNA to optimize liposome performance using modified amino acids, Dr. Adami reports. By varying the head-group, spacer, and alkylation of different amino acids, MDRNA is able to modulate the delivery properties of the DiLA2 in a liposomal formulation. Additionally, the DiLA2 platform can be combined with peptide-based nanoparticles that improve the efficiency of the delivered siRNAs.

    Dr. Adami will show data on the knockdown of various biomarkers in the liver, such as ApoB, DGAT2, and PSKC9, in the BALB/c mouse model. In these experiments, low doses of siRNA designed to knockdown these endogenously expressed targets in the liver were administered intravascularly for systemic delivery.

    MDRNA’s delivery platform, although liposome-based, can deliver siRNA to target organs other than the liver, Dr. Adami explains. As an example, he will show data on the use of this platform to deliver siRNAs to the urinary bladder through direct topical administration in a mouse model of orthotopic bladder cancer.

    “We are showing delivery to different, therapeutically relevant organs and demonstrating that applying mixed modality delivery systems can achieve successful gene knockdown in vivo,” he adds. “I think the impact will be that people in the field who tend to feel that there are few options for successful delivery will see that there really are opportunities using combinations of different kinds of molecules.” 

    Another liposome-based RNAi delivery developer, Silence Therapeutics, will have two presentations at the conference. Angsar Santel, Ph.D., senior scientist, will talk about the use of the AtuPLEX technology—a nonencapsulating, liposome-based siRNA delivery platform—in the delivery of therapeutic siRNAs to the vascular endothelium. The experiments were performed as a proof of concept for inhibiting gene expression in vascular endothelium as a means for treating popular endothelial diseases.

    Dr. Santel will present data from  experiments designed to study the endothelial dysfunction that is common in bacterial infections of the lung. “We are interested in identifying genes that are specifically upregulated in vascular endothelium in the lung upon bacterial infection,” he says. He will also show that downregulation of an identified target gene after systemic administration of AtuPLEX can be exploited for a therapeutic application.

    In the second presentation, Klaus Giese, Ph.D., CSO and vp of research, will show data on the firm’s lead RNAi therapeutic Atu027, an oncology drug that is scheduled to enter clinical trials this year. “From my point of view, it is clear that this is a novel treatment for angiogenesis, a therapeutic area that is rather novel in the field of RNA interference,” says Dr. Giese. “This will be the first program specifically designed to target tumor vasculature.”

    Tekmira Pharmaceuticals develops RNAi-based therapeutics that utilize its SNALP technology, a lipid-based nanoparticle system for delivering RNAi-based therapeutics systemically. “Systemic delivery really appears to require an appropriately designed delivery system. And it seems that a lot of diseases will be best addressed by systemic delivery,” says Ian MacLachlan, Ph.D., CSO, who will present recent preclinical work on an RNAi-based therapeutic targeting ApoB in the liver.

    Dr. MacLachlan will try to convey that Tekmira’s delivery technology is not only restricted to liver targets. “We have recently described not only the ability to deliver siRNA to the liver, but also the ability to extend the delivery to extrahepatic sites such as disseminated tumors,” he says. “The take-home message of my talk is that, through rational design of these lipid nanoparticles, we can design systems that enable safe and effective delivery of siRNA to different target tissues and for different indications.”

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