Knocking down disease: a progress report on siRNA therapeutics

Abstract

The key bottlenecks for small RNA drugs that harness RNA interference (RNAi) for selective gene knockdown in vivo include their delivery across the plasma membrane and their release from endosomes into the cytosol. Small interfering RNA (siRNA)-based drugs can now be delivered into the cytosol of hepatocytes to suppress gene expression in the liver. Recent siRNA clinical trials show durable and potent gene silencing in the liver, with manageable toxicity for a handful of disease targets. The most effective strategies for gene knockdown in the liver use second-generation lipid nanoparticles or GalNAc-conjugated siRNAs that are taken up by the asialoglycoprotein receptor, which is exclusively expressed by hepatocytes. Achieving gene knockdown outside the liver is still clinically unproven. The most attractive strategies use topical administration of siRNAs to accessible tissue sites, such as the skin, eye or mucosa, or use siRNAs that are covalently linked to an RNA aptamer that binds with high affinity to a cell surface receptor selectively expressed on cells being targeted for gene knockdown. Methods that are being developed to deliver siRNAs therapeutically may eventually prove to be useful for delivering other nucleic acid therapeutics, including antisense oligonucleotides, mRNAs for gene expression, or CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated 9) for gene editing.