UMMS Affiliation

RNA Therapeutics Institute; Program in Molecular Medicine; Horae Gene Therapy Center; Department of Microbiology and Physiological Systems; VIDE Program

Publication Date

2020-12-19

Document Type

Article

Disciplines

Biochemistry | Genetics and Genomics | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Therapeutics

Abstract

Oligonucleotide therapeutics hold promise for the treatment of muscle- and heart-related diseases. However, oligonucleotide delivery across the continuous endothelium of muscle tissue is challenging. Here, we demonstrate that docosanoic acid (DCA) conjugation of small interfering RNAs (siRNAs) enables efficient (~5% of injected dose), sustainable ( > 1 month), and non-toxic (no cytokine induction at 100 mg/kg) gene silencing in both skeletal and cardiac muscles after systemic injection. When designed to target myostatin (muscle growth regulation gene), siRNAs induced ~55% silencing in various muscle tissues and 80% silencing in heart, translating into a ~50% increase in muscle volume within 1 week. Our study identifies compounds for RNAi-based modulation of gene expression in skeletal and cardiac muscles, paving the way for both functional genomics studies and therapeutic gene modulation in muscle and heart.

Keywords

small interfering RNAs, siRNAs, oligonucleotide therapeutics, gene expression, skeletal muscles, cardiac muscles

Rights and Permissions

Copyright 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

DOI of Published Version

10.1016/j.ymthe.2020.12.023

Source

Biscans A, Caiazzi J, McHugh N, Hariharan V, Muhuri M, Khvorova A. Docosanoic acid conjugation to siRNA enables functional and safe delivery to skeletal and cardiac muscles. Mol Ther. 2020 Dec 19:S1525-0016(20)30681-X. doi: 10.1016/j.ymthe.2020.12.023. Epub ahead of print. PMID: 33348054. Link to article on publisher's site

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

Related Resources

Link to Article in PubMed

PubMed ID

33348054

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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