Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in <i>BTK</i> / <i>Tec</i> double deficient X-linked agammaglobulinemia model
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 (<i>BTK</i>). 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 <i>BTK</i> pre-mRNA. We further investigated the effect of conjugating cell-penetrating peptides, including Pip6a, to the SSOs. The effect was measured as splice-switching <i>in vitro</i> 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 <i>in vivo</i> 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.
Authors
- Oscar P. B. Wiklander (ORCID: https://orcid.org/0000-0003-1176-8114)
- Smith Rjh (ORCID: https://orcid.org/0000-0003-1907-3392)
- Anna Berglöf
- Christian J. Leumann (ORCID: https://orcid.org/0000-0002-7996-7083)
- H. Yesid Estupiñán (ORCID: https://orcid.org/0000-0002-9388-5957)
- Robert Månsson (ORCID: https://orcid.org/0000-0003-0738-0328)
- Samir EL Andaloussi (ORCID: https://orcid.org/0000-0003-4468-9113)
- Karin E. Lundin (ORCID: https://orcid.org/0000-0002-1489-3028)
- Rula Zain (ORCID: https://orcid.org/0000-0001-8327-846X)
- Chenfei He (ORCID: https://orcid.org/0000-0003-3373-8450)
- Taavi Lehto (ORCID: https://orcid.org/0000-0002-7131-2998)
- Frank Abendroth (ORCID: https://orcid.org/0000-0002-0320-2690)
- Dhanu Gupta (ORCID: https://orcid.org/0000-0003-0163-2678)
- Mikael C. I. Karlsson (ORCID: https://orcid.org/0000-0001-5582-614X)
- Burcu Bestas (ORCID: https://orcid.org/0000-0003-3990-1909)
- Jesper Wengel (ORCID: https://orcid.org/0000-0001-9835-1009)
- Dmitry A. Stetsenko (ORCID: https://orcid.org/0000-0002-5215-5704)
- Matthew J. A. Wood (ORCID: https://orcid.org/0000-0002-5436-6011)
- Qing Wang (ORCID: https://orcid.org/0009-0003-7328-8762)
- Mohammad H. Forouzanfar (ORCID: https://orcid.org/0000-0001-9201-0991)
- Michael J. Gait
- Shabnam Kharazi
Institutions
- Universidad Industrial de Santander (CO)
- University of Bern (CH)
- Karolinska University Hospital (SE)
- Philipps University of Marburg (DE)
- MRC Laboratory of Molecular Biology (GB)
- University of Southern Denmark (DK)
- Novosibirsk State University (RU)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- Institute of Cytology and Genetics (RU)
- University of Tartu (EE)
- Medical Research Council (GB)
Publication Details
- Journal
- RSC Chemical Biology
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d4cb00312h
- Citations
- 1
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Eesti Teadusagentuur
- Cancerfonden
- Ministry of Science and Higher Education of the Russian Federation
- Medical Research Council