Unknown

Dataset Information

0

Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo.


ABSTRACT: Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 ?g/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.

SUBMITTER: Biscans A 

PROVIDER: S-EPMC6379722 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo.

Biscans Annabelle A   Coles Andrew A   Haraszti Reka R   Echeverria Dimas D   Hassler Matthew M   Osborn Maire M   Khvorova Anastasia A  

Nucleic acids research 20190201 3


Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clear  ...[more]

Similar Datasets

| S-EPMC3898629 | biostudies-literature
| S-EPMC5096033 | biostudies-literature
| S-EPMC5498810 | biostudies-literature
| S-EPMC4111939 | biostudies-literature
| S-EPMC3955097 | biostudies-literature
| S-EPMC3470698 | biostudies-literature
| S-EPMC4307782 | biostudies-literature
| S-EPMC7116733 | biostudies-literature
| S-EPMC5910670 | biostudies-literature
| S-EPMC5308083 | biostudies-literature