Directed Alternative Splicing in Nijmegen Breakage Syndrome: Proof of Principle Concerning Its Therapeutical Application
| Autor: | Janina Radszewski, André Nussenzweig, Karl Sperling, Harald Krenzlin, Martin Digweed, Kerstin Borgmann, Gabriele Hildebrand, Ann Christin Parplys, Petra Wessendorf, Bastian Salewsky, Moritz Kieslich, Susanne Rothe |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA Replication Morpholino DNA damage Cell Cycle Proteins Biology Bioinformatics Cell Line 03 medical and health sciences Mice Drug Discovery medicine Genetics Animals Humans Child Nijmegen Breakage Syndrome Gene Molecular Biology Sequence Deletion Pharmacology Oligonucleotide Alternative splicing DNA replication Cancer Nuclear Proteins Middle Aged Oligonucleotides Antisense medicine.disease Alternative Splicing Disease Models Animal 030104 developmental biology embryonic structures Cancer research Molecular Medicine Female Original Article Nijmegen breakage syndrome |
| Zdroj: | Molecular Therapy. 24(1):117-124 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2015.144 |
| Popis: | Over 90% of patients with Nijmegen breakage syndrome (NBS), a hereditary cancer disorder, are homoallelic for a 5 bp deletion in the NBN gene involved in the cellular response to DNA damage. This hypomorphic mutation leads to a carboxy-terminal protein fragment, p70-nibrin, with some residual function. Average age at malignancy, typically lymphoma, is 9.7 years. NBS patients are hypersensitive to chemotherapeutic and radiotherapeutic treatments, thus prevention of cancer development is of particular importance. Expression of an internally deleted NBN protein, p80-nibrin, has been previously shown to be associated with a milder cellular phenotype and absence of cancer in a 62-year-old NBS patient. Here we show that cells from this patient, unlike other NBS patients, have DNA replication and origin firing rates comparable to control cells. We used here antisense oligonucleotides to enforce alternative splicing in NBS patient cells and efficiently generate the same internally deleted p80-nibrin protein. Injecting the same antisense sequences as morpholino oligomers (VivoMorpholinos) into the tail vein of a humanized NBS murine mouse model also led to efficient alternative splicing in vivo. Thus, proof of principle for the use of antisense oligonucleotides as a potential cancer prophylaxis has been demonstrated. |
| Databáze: | OpenAIRE |
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