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Feb 1, 2009 (Vol. 29, No. 3)

Improving Delivery of RNAi Drugs

Abundance of Vehicles Are in Development to Help Translate the Technology into Therapeutics

  • Chemical Modification Pattern

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    Accell siRNA reagents deliver effective knockdown without cytotoxicity, according to Thermo Scientific.

    Thermo Scientific began to focus on siRNA design a few years ago and developed a design algorithm to identify siRNAs for target genes that include all splice variants, while eliminating any undesirable sequences (such as SNPs), which interfere with siRNA performance. “As we better understand microRNA effects or seed-mediated silencing, it has become more important to incorporate criteria into siRNA design for specificity,” says Devin Leake, Ph.D., director of R&D, genomic technologies, Thermo Fisher Scientific.

    Thermo Scientific Dharmacon Accell™ siRNA incorporates a novel chemical modification pattern on the RNA duplex, allowing for cellular uptake without requiring transfection reagents or viral vectors. It has been shown to transfect common cell types like HeLA as well as difficult cell types like immune-derived cell lines.  “Once you start exploring chemical modifications on the siRNA design, you can compromise the other two desirable attributes: performance and specificity. The challenge we overcame is effectively addressing all three to have an siRNA that retains activity, specificity, and cellular uptake,” states Dr. Leake. This required a chemical modification pattern to help neutralize the negative charge of the phosphate backbone and to protect the duplex from degradation without any type of lipid formulation. The company is seeing success in animal models through academic collaborations.

    There’s no doubt that RNAi has quickly advanced from its initial discovery in worms to a key genetic research tool, and now, perhaps one of the most promising novel therapeutics with the potential to change the future of medicine. Despite the somewhat major hurdles that exist, delivery being the key one, Big Pharma is betting on it.

    GlaxoSmithKline recently signed a $600 million collaboration agreement with Regulus. Alnylam has milestone deals ranging from $700 million to more than $1 billion with Novartis and Roche, respectfully. Merck bought Sirna Therapeutics for $1.1 billion. That translates into a lot of faith in RNAi, which may take years to realize.

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