Conjugation of hydrophobic moieties enhances potency of antisense oligonucleotides in the muscle of rodents and non-human primates.
3T3-L1 Cells
Albumins
/ metabolism
Animals
Cholesterol
/ chemistry
Hydrophobic and Hydrophilic Interactions
Lipoproteins
/ metabolism
Macaca fascicularis
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Muscle, Skeletal
Myocardium
Oligonucleotides, Antisense
/ chemistry
Palmitates
/ chemistry
Rats, Sprague-Dawley
Tocopherols
/ chemistry
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
09 07 2019
09 07 2019
Historique:
accepted:
26
04
2019
revised:
18
04
2019
received:
22
03
2019
pubmed:
12
5
2019
medline:
26
2
2020
entrez:
12
5
2019
Statut:
ppublish
Résumé
We determined the effect of attaching palmitate, tocopherol or cholesterol to PS ASOs and their effects on plasma protein binding and on enhancing ASO potency in the muscle of rodents and monkeys. We found that cholesterol ASO conjugates showed 5-fold potency enhancement in the muscle of rodents relative to unconjugated ASOs. However, they were toxic in mice and as a result were not evaluated in the monkey. In contrast, palmitate and tocopherol-conjugated ASOs showed enhanced potency in the skeletal muscle of rodents and modest enhancements in potency in the monkey. Analysis of the plasma-protein binding profiles of the ASO-conjugates by size-exclusion chromatography revealed distinct and species-specific differences in their association with plasma proteins which likely rationalizes their behavior in animals. Overall, our data suggest that modulating binding to plasma proteins can influence ASO activity and distribution to extra-hepatic tissues in a species-dependent manner and sets the stage to identify other strategies to enhance ASO potency in muscle tissues.
Identifiants
pubmed: 31076766
pii: 5488020
doi: 10.1093/nar/gkz360
pmc: PMC6614849
doi:
Substances chimiques
Albumins
0
Lipoproteins
0
Oligonucleotides, Antisense
0
Palmitates
0
Cholesterol
97C5T2UQ7J
Tocopherols
R0ZB2556P8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6045-6058Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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