RT Journal Article SR Electronic T1 Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo JF bioRxiv FD Cold Spring Harbor Laboratory SP 289439 DO 10.1101/289439 A1 Annabelle Biscans A1 Andrew Coles A1 Reka Haraszti A1 Dimas Echeverria A1 Matthew Hassler A1 Maire Osborn A1 Anastasia Khvorova YR 2018 UL http://biorxiv.org/content/early/2018/03/26/289439.abstract AB RNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulation in vivo in lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.