Docosanoic acid conjugation to siRNA enables functional and safe delivery to skeletal and cardiac muscles
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Authors
Biscans, AnnabelleCaiazzi, Jillian
McHugh, Nicholas
Hariharan, Vignesh
Muhuri, Manish
Khvorova, Anastasia
UMass Chan Affiliations
VIDE ProgramDepartment of Microbiology and Physiological Systems
Horae Gene Therapy Center
Program in Molecular Medicine
RNA Therapeutics Institute
Document Type
Journal ArticlePublication Date
2020-12-19Keywords
small interfering RNAssiRNAs
oligonucleotide therapeutics
gene expression
skeletal muscles
cardiac muscles
Biochemistry
Genetics and Genomics
Medicinal Chemistry and Pharmaceutics
Medicinal-Pharmaceutical Chemistry
Therapeutics
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Show full item recordAbstract
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.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
DOI
10.1016/j.ymthe.2020.12.023Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41723PubMed ID
33348054Related Resources
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Copyright 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.ymthe.2020.12.023
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Except where otherwise noted, this item's license is described as Copyright 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/