title: Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth.
abstract: Short interfering RNAs (siRNAs) are a valuable tool for gene silencing with applications in both target validation and therapeutics. Many advances have recently been made to improve potency and specificity, and reduce toxicity and immunostimulation. However, siRNA delivery to a variety of tissues remains an obstacle for this technology. To date, siRNA delivery to muscle has only been achieved by local administration or by methods with limited potential use in the clinic. We report systemic delivery of a highly chemically modified cholesterol-conjugated siRNA targeting muscle-specific gene myostatin (Mstn) to a full range of muscles in mice. Following a single intravenous injection, we observe 85-95% knockdown of Mstn mRNA in skeletal muscle and >65% reduction in circulating Mstn protein sustained for >21 days. This level of Mstn knockdown is also accompanied by a functional effect on skeletal muscle, with animals showing an increase in muscle mass, size, and strength. The cholesterol-conjugated siRNA platform described here could have major implications for treatment of a variety of muscle disorders, including muscular atrophic diseases, muscular dystrophy, and type II diabetes.
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Tayeba
authors.initials: T
authors.lastname: Khan
authors.affiliation: Department of In Vivo Pharmacology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Weber
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: DiMuzio
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Matter
authors.affiliation: Department of Applied Mathematics and Modeling- Scientific Informatics, Merck and Co., Inc, Rahway, New Jersey, USA.
authors.forename: Belma
authors.initials: B
authors.lastname: Dogdas
authors.affiliation: Department of Applied Mathematics and Modeling- Scientific Informatics, Merck and Co., Inc, Rahway, New Jersey, USA.
authors.forename: Tosha
authors.initials: T
authors.lastname: Shah
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Thankappan
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck and Co., Inc, Boston, Massachusetts, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Disa
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Vasant
authors.initials: V
authors.lastname: Jadhav
authors.affiliation: Department of In Vivo Pharmacology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Lubbers
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.affiliation: Department of RNA Therapeutics Discovery Biology, Merck and Co., Inc, West Point, Pennsylvania, USA.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Strapps
authors.affiliation: Department of Genetics and Pharmacogenomics, Merck and Co., Inc, Boston, Massachusetts, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps