ArticleThe Journal of clinical investigation2014
Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 47 citations in OpenAlex.
- Outcomes of X-Linked Agammaglobulinaemia Patients.Journal of clinical immunology · 2024Article
- Hematopoietic stem cell gene editing rescues B-cell development in X-linked agammaglobulinemia.The Journal of allergy and clinical immunology · 2024Article
- Severe Tick-Borne Encephalitis (TBE) in a Patient with X-Linked Agammaglobulinemia; Treatment with TBE Virus IgG Positive Plasma, Clinical Outcome and T Cell Responses.Journal of clinical immunology · 2024Article
- Neutralizing SARS-CoV-2 Antibodies in Commercial Immunoglobulin Products Give Patients with X-Linked Agammaglobulinemia Limited Passive Immunity to the Omicron Variant.Journal of clinical immunology · 2022Article
- 2'-Nucleic acid therapeutics · 2022Article
- Divalent Metal Ions Boost Effect of Nucleic Acids Delivered by Cell-Penetrating Peptides.Cells · 2022Article
- Design and In Vitro Evaluation of Splice-Switching Oligonucleotides Bearing Locked Nucleic Acids, Amido-Bridged Nucleic Acids, and Guanidine-Bridged Nucleic Acids.International journal of molecular sciences · 2021Article
- Primary Immunodeficiencies: Diseases of Children and Adults - A Review.Advances in experimental medicine and biology · 2021Review
- Advances in oligonucleotide drug delivery.Nature reviews. Drug discovery · 2020Review
- Novel mouse model resistant to irreversible BTK inhibitors: a tool identifying new therapeutic targets and side effects.Blood advances · 2020Article
- Uncoupling Splicing From Transcription Using Antisense Oligonucleotides Reveals a Dual Role for I Exon Donor Splice Sites in Antibody Class Switching.Frontiers in immunology · 2020Article
- Sugar and Polymer Excipients Enhance Uptake and Splice-Switching Activity of Peptide-Dendrimer/Lipid/Oligonucleotide Formulations.Pharmaceutics · 2019Article
- PEGylation of therapeutic oligonucletides: From linear to highly branched PEG architectures.Nano research · 2018Article
- Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy.Genes · 2018Article
- Hydrogel-Assisted Antisense LNA Gapmer Delivery for In Situ Gene Silencing in Spinal Cord Injury.Molecular therapy. Nucleic acids · 2018Article
- IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation.Journal of clinical immunology · 2018Article
- CTG repeat-targeting oligonucleotides for down-regulating Huntingtin expression.Nucleic acids research · 2017Article
- Evolving Gene Therapy in Primary Immunodeficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2017Review
- Splice-switching antisense oligonucleotides as therapeutic drugs.Nucleic acids research · 2016Review
- Oligonucleotide Therapies: The Past and the Present.Human gene therapy · 2015Review
Corrections and comments
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Authors and funding
21 authors at 11 institutions in 6 countries.
Funding
Abstract
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 BTK transcripts 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.