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Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model. / Bestas, Burcu; Estupiñán, H. Yesid; Wang, Qing et al.

In: RSC Chemical Biology, 2025.

Research output: Contribution to journal › Article › peer-review

Harvard

Bestas, B, Estupiñán, HY, Wang, Q, Kharazi, S, He, C, K. Mohammad, D, Gupta, D, Wiklander, OPB, Lehto, T, Lundin, KE, Berglöf, A, Karlsson, MCI, Abendroth, F, El Andaloussi, S, Gait, MJ, Wood, MJA, Leumann, CJ, Stetsenko, DA, Månsson, R, Wengel, J, Zain, R & Smith, CIE 2025, 'Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model', RSC Chemical Biology. https://doi.org/10.1039/d4cb00312h

APA

Bestas, B., Estupiñán, H. Y., Wang, Q., Kharazi, S., He, C., K. Mohammad, D., Gupta, D., Wiklander, O. P. B., Lehto, T., Lundin, K. E., Berglöf, A., Karlsson, M. C. I., Abendroth, F., El Andaloussi, S., Gait, M. J., Wood, M. J. A., Leumann, C. J., Stetsenko, D. A., Månsson, R., ... Smith, C. I. E. (2025). Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model. RSC Chemical Biology. https://doi.org/10.1039/d4cb00312h

Vancouver

Bestas B, Estupiñán HY, Wang Q, Kharazi S, He C, K. Mohammad D et al. Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model. RSC Chemical Biology. 2025. doi: 10.1039/d4cb00312h

Author

Bestas, Burcu ; Estupiñán, H. Yesid ; Wang, Qing et al. / Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model. In: RSC Chemical Biology. 2025.

BibTeX

@article{0d8d0ebb2b0e418383703e482f8b8b1d,
title = "Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model",
abstract = "Splice-switching oligonucleotides (SSOs) have been developed as a treatment for various disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Here, the activity of several different SSOs was investigated as potential treatments for B lymphocyte disorders with a focus on X-linked agammaglobulinemia (XLA), caused by defects in the gene encoding Bruton's tyrosine kinase (BTK). In this study, the activity of locked nucleic acid (LNA), tricyclo-DNA (tcDNA), phosphoryl guanidine oligonucleotides (PGO) and phosphorodiamidate morpholino oligomers (PMO) were compared, targeting the pseudoexon region of BTK pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching in vitro as well as in a further developed, bacterial artificial chromosome transgenic mouse model of XLA. Therapy in the form of intravenous infusions 2 times a week during 3 weeks of PMO oligomers conjugated to Pip6a was sufficient to partly restore the in vivo B lineage phenotype. SSOs treatment also provides a unique opportunity to get insights into a restoration process, when B lymphocytes of different maturation stages are simultaneously splice-corrected.",
author = "Burcu Bestas and Estupi{\~n}{\'a}n, {H. Yesid} and Qing Wang and Shabnam Kharazi and Chenfei He and {K. Mohammad}, Dara and Dhanu Gupta and Wiklander, {Oscar P.B.} and Taavi Lehto and Lundin, {Karin E.} and Anna Bergl{\"o}f and Karlsson, {Mikael C.I.} and Frank Abendroth and {El Andaloussi}, Samir and Gait, {Michael J.} and Wood, {Matthew J.A.} and Leumann, {Christian J.} and Stetsenko, {Dmitry A.} and Robert M{\aa}nsson and Jesper Wengel and Rula Zain and Smith, {C. I.Edvard}",
note = "This work was supported by the Swedish Cancer Society and the Swedish Medical Research Council. T. L. is supported by Estonian Research Council (PUTJD71 and PRG1882). D. A. S. is supported by the Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk state University no. FSUS-2025-0012). We thank Wilfried Ellmeier for providing us the BTK/Tec double deficient mouse strain. ",
year = "2025",
doi = "10.1039/d4cb00312h",
language = "English",
journal = "RSC Chemical Biology",
issn = "2633-0679",
publisher = "Royal Society of Chemistry",

}

RIS

TY - JOUR

T1 - Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model

AU - Bestas, Burcu

AU - Estupiñán, H. Yesid

AU - Wang, Qing

AU - Kharazi, Shabnam

AU - He, Chenfei

AU - K. Mohammad, Dara

AU - Gupta, Dhanu

AU - Wiklander, Oscar P.B.

AU - Lehto, Taavi

AU - Lundin, Karin E.

AU - Berglöf, Anna

AU - Karlsson, Mikael C.I.

AU - Abendroth, Frank

AU - El Andaloussi, Samir

AU - Gait, Michael J.

AU - Wood, Matthew J.A.

AU - Leumann, Christian J.

AU - Stetsenko, Dmitry A.

AU - Månsson, Robert

AU - Wengel, Jesper

AU - Zain, Rula

AU - Smith, C. I.Edvard

N1 - This work was supported by the Swedish Cancer Society and the Swedish Medical Research Council. T. L. is supported by Estonian Research Council (PUTJD71 and PRG1882). D. A. S. is supported by the Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk state University no. FSUS-2025-0012). We thank Wilfried Ellmeier for providing us the BTK/Tec double deficient mouse strain.

PY - 2025

Y1 - 2025

N2 - Splice-switching oligonucleotides (SSOs) have been developed as a treatment for various disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Here, the activity of several different SSOs was investigated as potential treatments for B lymphocyte disorders with a focus on X-linked agammaglobulinemia (XLA), caused by defects in the gene encoding Bruton's tyrosine kinase (BTK). In this study, the activity of locked nucleic acid (LNA), tricyclo-DNA (tcDNA), phosphoryl guanidine oligonucleotides (PGO) and phosphorodiamidate morpholino oligomers (PMO) were compared, targeting the pseudoexon region of BTK pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching in vitro as well as in a further developed, bacterial artificial chromosome transgenic mouse model of XLA. Therapy in the form of intravenous infusions 2 times a week during 3 weeks of PMO oligomers conjugated to Pip6a was sufficient to partly restore the in vivo B lineage phenotype. SSOs treatment also provides a unique opportunity to get insights into a restoration process, when B lymphocytes of different maturation stages are simultaneously splice-corrected.

AB - Splice-switching oligonucleotides (SSOs) have been developed as a treatment for various disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Here, the activity of several different SSOs was investigated as potential treatments for B lymphocyte disorders with a focus on X-linked agammaglobulinemia (XLA), caused by defects in the gene encoding Bruton's tyrosine kinase (BTK). In this study, the activity of locked nucleic acid (LNA), tricyclo-DNA (tcDNA), phosphoryl guanidine oligonucleotides (PGO) and phosphorodiamidate morpholino oligomers (PMO) were compared, targeting the pseudoexon region of BTK pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching in vitro as well as in a further developed, bacterial artificial chromosome transgenic mouse model of XLA. Therapy in the form of intravenous infusions 2 times a week during 3 weeks of PMO oligomers conjugated to Pip6a was sufficient to partly restore the in vivo B lineage phenotype. SSOs treatment also provides a unique opportunity to get insights into a restoration process, when B lymphocytes of different maturation stages are simultaneously splice-corrected.

UR - https://www.mendeley.com/catalogue/3448e2bc-a19f-37af-9fb0-78fffa28fd22/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-105001724997&origin=inward&txGid=ca9800c8fc0e1c8823431b2e37599b28

U2 - 10.1039/d4cb00312h

DO - 10.1039/d4cb00312h

M3 - Article

C2 - 40171248

JO - RSC Chemical Biology

JF - RSC Chemical Biology

SN - 2633-0679

ER -

ID: 65194774