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RNAi-based therapeutic strategies for metabolic disease

Nature Reviews Endocrinology volume 7, pages 473–484 (2011)Cite this article

Subjects

Abstract

RNA interference (RNAi) is a robust gene silencing mechanism that degrades mRNAs complementary to the antisense strands of double-stranded, short interfering RNAs (siRNAs). As a therapeutic strategy, RNAi has an advantage over small-molecule drugs, as virtually all genes are susceptible to targeting by siRNA molecules. This advantage is, however, counterbalanced by the daunting challenge of achieving safe, effective delivery of oligonucleotides to specific tissues in vivo. Lipid-based carriers of siRNA therapeutics can now target the liver in metabolic diseases and are being assessed in clinical trials for the treatment of hypercholesterolemia. For this indication, a chemically modified oligonucleotide that targets endogenous small RNA modulators of gene expression (microRNAs) is also under investigation in clinical trials. Emerging 'self-delivery' siRNAs that are covalently linked to lipophilic moieties show promise for the future development of therapies. Besides the liver, inflammation of the adipose tissue in patients with obesity and type 2 diabetes mellitus may be an attractive target for siRNA therapeutics. Administration of siRNAs encapsulated within glucan microspheres can silence genes in inflammatory phagocytic cells, as can certain lipid-based carriers of siRNA. New technologies that combine siRNA molecules with antibodies or other targeting molecules also appear encouraging. Although still at an early stage, the emergence of RNAi-based therapeutics has the potential to markedly influence our clinical future.

Key Points

  • RNA interference (RNAi) represents a therapeutic approach for targeting any expressed gene with a high degree of specificity

  • Chemical modifications of siRNAs enhance their potency, stability and efficacy, while reducing immunostimulatory effects

  • Targeting hepatic lipid synthesis with RNAi can alleviate hyperlipidemia and hepatic steatosis in patients with the metabolic syndrome

  • Clinical trials have shown that liposomal RNAi delivery systems are efficacious at lowering serum lipid profiles

  • The metabolic syndrome in patients with obesity is associated with adipose tissue inflammation

  • Targeting inflammation with RNAi may offer an exciting but challenging goal for the treatment of metabolic disease

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Figure 1: Major steps in the RNA interference (RNAi) pathway.
Figure 2: Physiological barriers to successful delivery of small RNA therapeutics in humans.
Figure 3: Modifications of small RNA therapeutics that enhance potency or decrease susceptibility to nucleases, innate immune responses and off-target effects.
Figure 4: Targets in hepatic signaling pathways in metabolic disease.
Figure 5: Obesity leads to inflammation and insulin resistance in adipose tissue.

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Acknowledgements

The authors thank the members of their laboratory group for excellent discussions on the issues addressed in this Review. The studies from the authors' laboratory covered in this Review were supported by grants to M. P. Czech from the NIH (DK30898 and DK085753), a Juvenile Diabetes Research Foundation Award (17-2009-546) and by Core Facilities in the University of Massachusetts Diabetes and Endocrinology Research Center also funded by the NIH (DK325220).

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  1. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, 01605, MA, USA

    Michael P. Czech, Myriam Aouadi & Gregory J. Tesz

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All authors researched the data for the article, provided a substantial contribution to discussions of the content, contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

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M. P. Czech declares an association with the following company: RXi Pharmaceuticals (stockholder/director, patent holder). M. Aouadi declares an association with the following company: RXi Pharmaceuticals (patent holder), G. J. Tesz declares no competing interests.

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Czech, M., Aouadi, M. & Tesz, G. RNAi-based therapeutic strategies for metabolic disease. Nat Rev Endocrinol 7, 473–484 (2011). https://doi.org/10.1038/nrendo.2011.57

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