Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides

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Fältnamn	Indikatorer	Metadata
000		04893naa a2200649 4500
001		oai:research.chalmers.se:324936bc-3a36-49af-83bc-1c8a6108c72f
003		SwePub
008		220311s2022 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:prod.swepub.kib.ki.se:148971700
024	7	a https://doi.org/10.1038/s42003-022-03132-22 DOI
024	7	a https://research.chalmers.se/publication/5290102 URI
024	7	a http://kipublications.ki.se/Default.aspx?queryparsed=id:1489717002 URI
040		a (SwePub)cthd (SwePub)ki
041		a engb eng
042		9 SwePub
072	7	a art2 swepub-publicationtype
072	7	a ref2 swepub-contenttype
100	1	a Bost, Jeremy P.u Karolinska Institutet4 aut
245	1 0	a Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides
264		c 2022-03-01
264	1	b Springer Science and Business Media LLC,c 2022
338		a electronic2 rdacarrier
520		a 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.
650	7	a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe
650	7	a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Läkemedelskemi0 (SwePub)301032 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Medicinal Chemistry0 (SwePub)301032 hsv//eng
650	7	a NATURVETENSKAPx Kemix Organisk kemi0 (SwePub)104052 hsv//swe
650	7	a NATURAL SCIENCESx Chemical Sciencesx Organic Chemistry0 (SwePub)104052 hsv//eng
700	1	a Ojansivu, Miinau Karolinska Institutet4 aut
700	1	a Munson, Michael J.u AstraZeneca AB4 aut
700	1	a Vilhelmsson Wesén, Emelie,d 1989u Chalmers tekniska högskola,Chalmers University of Technology4 aut0 (Swepub:cth)emelin
700	1	a Gallud, Audrey,d 1988u Chalmers tekniska högskola,Chalmers University of Technology,AstraZeneca AB4 aut0 (Swepub:cth)gallud
700	1	a Gupta, Dhanuu Karolinska Institutet4 aut
700	1	a Gustafsson, Oskaru Karolinska Institutet4 aut
700	1	a Saher, Osamau Karolinska Institutet4 aut
700	1	a Rädler, Juliau Karolinska Institutet4 aut
700	1	a Higgins, Stuart G.u Imperial College of Science, Technology and Medicine4 aut
700	1	a Lehto, Taaviu Karolinska Institutet4 aut
700	1	a Holme, Margaret N.u Karolinska Institutet4 aut
700	1	a Dahlén, Andersu AstraZeneca AB4 aut
700	1	a Engkvist, Olau AstraZeneca AB4 aut
700	1	a Strömstedt, Per Eriku AstraZeneca AB4 aut
700	1	a Andersson, Shaliniu AstraZeneca AB4 aut
700	1	a Edvard Smith, C. I.u Karolinska Institutet4 aut
700	1	a Stevens, Molly M.u Karolinska Institutet4 aut
700	1	a Esbjörner Winters, Elin,d 1978u Chalmers tekniska högskola,Chalmers University of Technology4 aut0 (Swepub:cth)eline
700	1	a Collén, Annau AstraZeneca AB4 aut
700	1	a El-Andaloussi, Samiru Karolinska Institutet4 aut
700	1	a Esbjorner, EK4 aut
710	2	a Karolinska Institutetb AstraZeneca AB4 org
773	0	t Communications Biologyd : Springer Science and Business Media LLCg 5:1q 5:1x 2399-3642
856	4	u https://research.chalmers.se/publication/529010/file/529010_Fulltext.pdfx primaryx freey FULLTEXT
856	4	u https://www.nature.com/articles/s42003-022-03132-2.pdf
856	4 8	u https://doi.org/10.1038/s42003-022-03132-2
856	4 8	u https://research.chalmers.se/publication/529010
856	4 8	u http://kipublications.ki.se/Default.aspx?queryparsed=id:148971700

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