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LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00003881naa a2200565 4500
001oai:DiVA.org:su-107799
003SwePub
008140929s2014 | |||||||||||000 ||eng|
009oai:prod.swepub.kib.ki.se:129655940
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-1077992 URI
0247 a https://doi.org/10.1172/JCI761752 DOI
0247 a http://kipublications.ki.se/Default.aspx?queryparsed=id:1296559402 URI
040 a (SwePub)sud (SwePub)ki
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Bestas, Burcuu Karolinska Institutet4 aut
2451 0a Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
264 1c 2014
338 a print2 rdacarrier
500 a AuthorCount:21;
520 a X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinsk bioteknologi0 (SwePub)3042 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Medical Biotechnology0 (SwePub)3042 hsv//eng
7001 a Moreno, Pedro M. D.4 aut
7001 a Blomberg, K. Emelie M.u Karolinska Institutet4 aut
7001 a Mohammad, Dara K.u Karolinska Institutet4 aut
7001 a Saleh, Amer F.4 aut
7001 a Sutlu, Tolga4 aut
7001 a Nordin, Joel Z.u Karolinska Institutet4 aut
7001 a Guterstam, Peteru Stockholms universitet,Institutionen för neurokemi4 aut
7001 a Gustafsson, Manuela O.u Karolinska Institutet4 aut
7001 a Kharazi, Shabnamu Karolinska Institutet4 aut
7001 a Piatosa, Barbara4 aut
7001 a Roberts, Thomas C.4 aut
7001 a Behlke, Mark A.4 aut
7001 a Wood, Matthew J. A.4 aut
7001 a Gait, Michael J.4 aut
7001 a Lundin, Karin E.u Karolinska Institutet4 aut
7001 a EL Andaloussi, Samiru Karolinska Institutet4 aut
7001 a Mansson, Robertu Karolinska Institutet4 aut
7001 a Berglof, Annau Karolinska Institutet4 aut
7001 a Wengel, Jesper4 aut
7001 a Smith, C. I. Edvardu Karolinska Institutet4 aut
7102 a Karolinska Institutetb Institutionen för neurokemi4 org
7730 t Journal of Clinical Investigationg 124:9, s. 4067-4081q 124:9<4067-4081x 0021-9738x 1558-8238
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-107799
8564 8u https://doi.org/10.1172/JCI76175
8564 8u http://kipublications.ki.se/Default.aspx?queryparsed=id:129655940

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