Imperial College London
Alternate

Professor Molly Stevens

Faculty of Engineering, Department of Materials

Professor of Biomedical Materials and Regenerative Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6804m.stevens

 
 
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Location

 

208Royal School of MinesSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bost:2022:10.1038/s42003-022-03132-2,
author = {Bost, JP and Ojansivu, M and Munson, MJ and Wesén, E and Gallud, A and Gupta, D and Gustafsson, O and Saher, O and Rädler, J and Higgins, SG and Lehto, T and Holme, MN and Dahlén, A and Engkvist, O and Strömstedt, P-E and Andersson, S and Edvard, Smith CI and Stevens, MM and Esbjörner, EK and Collén, A and El, Andaloussi S},
doi = {10.1038/s42003-022-03132-2},
journal = {Communications Biology},
title = {Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides},
url = {http://dx.doi.org/10.1038/s42003-022-03132-2},
volume = {5},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs.
AU  - Bost,JP
AU  - Ojansivu,M
AU  - Munson,MJ
AU  - Wesén,E
AU  - Gallud,A
AU  - Gupta,D
AU  - Gustafsson,O
AU  - Saher,O
AU  - Rädler,J
AU  - Higgins,SG
AU  - Lehto,T
AU  - Holme,MN
AU  - Dahlén,A
AU  - Engkvist,O
AU  - Strömstedt,P-E
AU  - Andersson,S
AU  - Edvard,Smith CI
AU  - Stevens,MM
AU  - Esbjörner,EK
AU  - Collén,A
AU  - El,Andaloussi S
DO  - 10.1038/s42003-022-03132-2
PY  - 2022///
SN  - 2399-3642
TI  - Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides
T2  - Communications Biology
UR  - http://dx.doi.org/10.1038/s42003-022-03132-2
UR  - https://www.ncbi.nlm.nih.gov/pubmed/35233031
UR  - http://hdl.handle.net/10044/1/95627
VL  - 5
ER  -
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