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Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice
Conjugation of antisense oligonucleotide (ASO) with a variety of distinct lipophilic moieties like fatty acids and cholesterol increases ASO accumulation and activity in multiple tissues. While lipid conjugation increases tissue exposure in mice and reduces excretion of ASO in urine, histological re...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192618/ https://www.ncbi.nlm.nih.gov/pubmed/32182359 http://dx.doi.org/10.1093/nar/gkaa164 |
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author | Chappell, Alfred E Gaus, Hans J Berdeja, Andres Gupta, Ruchi Jo, Minji Prakash, Thazha P Oestergaard, Michael Swayze, Eric E Seth, Punit P |
author_facet | Chappell, Alfred E Gaus, Hans J Berdeja, Andres Gupta, Ruchi Jo, Minji Prakash, Thazha P Oestergaard, Michael Swayze, Eric E Seth, Punit P |
author_sort | Chappell, Alfred E |
collection | PubMed |
description | Conjugation of antisense oligonucleotide (ASO) with a variety of distinct lipophilic moieties like fatty acids and cholesterol increases ASO accumulation and activity in multiple tissues. While lipid conjugation increases tissue exposure in mice and reduces excretion of ASO in urine, histological review of skeletal and cardiac muscle indicates that the increased tissue accumulation of lipid conjugated ASO is isolated to the interstitium. Administration of palmitic acid-conjugated ASO (Palm-ASO) in mice results in a rapid and substantial accumulation in the interstitium of muscle tissue followed by relatively rapid clearance and only slight increases in intracellular accumulation in myocytes. We propose a model whereby increased affinity for lipid particles, albumin, and other plasma proteins by lipid-conjugation facilitates ASO transport across endothelial barriers into tissue interstitium. However, this increased affinity for lipid particles and plasma proteins also facilitates the transport of ASO from the interstitium to the lymph and back into circulation. The cumulative effect is only a slight (∼2-fold) increase in tissue accumulation and similar increase in ASO activity. To support this proposal, we demonstrate that the activity of lipid conjugated ASO was reduced in two mouse models with defects in endothelial transport of macromolecules: caveolin-1 knockout (Cav1(−/−)) and FcRn knockout (FcRn(−/−)). |
format | Online Article Text |
id | pubmed-7192618 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-71926182020-05-06 Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice Chappell, Alfred E Gaus, Hans J Berdeja, Andres Gupta, Ruchi Jo, Minji Prakash, Thazha P Oestergaard, Michael Swayze, Eric E Seth, Punit P Nucleic Acids Res Molecular Biology Conjugation of antisense oligonucleotide (ASO) with a variety of distinct lipophilic moieties like fatty acids and cholesterol increases ASO accumulation and activity in multiple tissues. While lipid conjugation increases tissue exposure in mice and reduces excretion of ASO in urine, histological review of skeletal and cardiac muscle indicates that the increased tissue accumulation of lipid conjugated ASO is isolated to the interstitium. Administration of palmitic acid-conjugated ASO (Palm-ASO) in mice results in a rapid and substantial accumulation in the interstitium of muscle tissue followed by relatively rapid clearance and only slight increases in intracellular accumulation in myocytes. We propose a model whereby increased affinity for lipid particles, albumin, and other plasma proteins by lipid-conjugation facilitates ASO transport across endothelial barriers into tissue interstitium. However, this increased affinity for lipid particles and plasma proteins also facilitates the transport of ASO from the interstitium to the lymph and back into circulation. The cumulative effect is only a slight (∼2-fold) increase in tissue accumulation and similar increase in ASO activity. To support this proposal, we demonstrate that the activity of lipid conjugated ASO was reduced in two mouse models with defects in endothelial transport of macromolecules: caveolin-1 knockout (Cav1(−/−)) and FcRn knockout (FcRn(−/−)). Oxford University Press 2020-05-07 2020-03-17 /pmc/articles/PMC7192618/ /pubmed/32182359 http://dx.doi.org/10.1093/nar/gkaa164 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular Biology Chappell, Alfred E Gaus, Hans J Berdeja, Andres Gupta, Ruchi Jo, Minji Prakash, Thazha P Oestergaard, Michael Swayze, Eric E Seth, Punit P Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title | Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title_full | Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title_fullStr | Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title_full_unstemmed | Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title_short | Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
title_sort | mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192618/ https://www.ncbi.nlm.nih.gov/pubmed/32182359 http://dx.doi.org/10.1093/nar/gkaa164 |
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