Shutting down the messenger: Antisense treatment for hypertriglyceridemia

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Science Translational Medicine  12 Aug 2015:
Vol. 7, Issue 300, pp. 300ec140
DOI: 10.1126/scitranslmed.aad0228

Antisense oligonucleotides (ASOs) are short (12 to 20) nucleic acid sequences that can bind to messenger RNA (mRNA) via Watson-Crick hybridization. Such binding inactivates the bound mRNA, effectively turning off the corresponding gene. Many human illnesses are caused by aberrant protein expression and signaling; therefore, these agents hold high potential to revolutionize the treatment of many human diseases.

Although they were highly promising, the first generation of ASOs showed little therapeutic benefit because of their short half-lives, suboptimal affinity for mRNA, and poor tissue penetration. To overcome these limitations, newer ASOs are chemically modified to improve stability. Common modifications include replacing phosphates in the backbone with phosphorothioates and modifying the sugar moiety of the nucleic acids. Although recent interest in nucleic acid–based therapies has focused mainly on RNAi technology, the robust clinical results from ASO therapeutics are shifting the focus back to this class of agents.

The study by Gaudet et al. is a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 clinical trial examining ISIS 304801, an ASO targeting apolipoprotein C-III (APOC3), in patients with hypertriglyceridemia. A total of 85 patients were enrolled in two cohorts (ISIS 304801 only and ISIS 304801-fibrate). Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 concentration in both cohorts. The investigators also observed concordant reductions (31.3% to 70.9%) in triglyceride concentrations.

The results from this study suggest that ISIS 304801 is a highly promising therapy for hypertriglyceridemia, although these findings will need to be validated in a larger randomized phase III trial. Importantly, there is renewed excitement in the development of ASO therapeutics because of these promising data on ISIS 304801 as well as other ASO drugs. Future research should focus on how to optimize ASO therapeutics for each disease condition.

D. Gaudet et al., Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373, 438–447 (2015). [Abstract]

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