Synthetic small interfering RNAs (siRNAs) are potent inhibitors of gene expression; these agents act through the natural RNA interference (RNAi) pathway. Although much hope and speculation regarding the therapeutic potential of RNAi began soon after the discovery of the pathway (Alnylam was founded in 2002), there have been challenges in realizing this potential, most related to difficulties in efficient delivery into the cells of specific organs or tissues. To deliver siRNAs into liver hepatocytes, we have developed a three-pronged approach with the goals of enabling delivery to hepatocytes after both intravenous and subcutaneous administration. These methods include chemical modification of siRNAs, lipid nanoparticle (LNP) formulation of siRNAs, and multivalent N-acetylgalactosamine (GalNAc) conjugation of siRNAs. The LNP strategy with a partially chemically modified siRNA resulted in the first RNAi therapeutic approved by the US FDA in 2018. This drug, ONPATTRO®, is used to treat polyneuropathy in patients with hereditary ATTR amyloidosis. The approval of ONPATTRO® paves the way for a whole new class of RNA-based medicines. Several GalNAc-conjugated siRNAs are currently performing well with promising outcome in the ongoing advanced clinical trials.

How sweet it is to work with sugars: Success story of carbohydrates conjugates of sugar-modified RNAs to make life-saving drugs

2019 Fall National Meeting

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