Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations
| Autor: | Gerard Platenburg, Jingjing Zang, Erwin van Wijk, Margo Dona, Sanne Broekman, Jiayi Miao, Cathaline den Besten, Erik de Vrieze, Hee Lam Chan, Janne J. Turunen, Hanka Venselaar, Lars Vorthoren, Kalyan Dulla, Peter Adamson, Ralph Slijkerman, Stephan C.F. Neuhauss, Silvia Albert, Wouter Beumer, Theo A. Peters, Iris Schmidt, Hester van Diepen, Ronald J.E. Pennings, Hannie Kremer, Levi Buil, Iris Schulkens |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Usher syndrome Mutant Induced Pluripotent Stem Cells Biology medicine.disease_cause Retina Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] 03 medical and health sciences Exon Mice 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center Drug Discovery Retinitis pigmentosa otorhinolaryngologic diseases Genetics medicine Animals Humans Outer nuclear layer Molecular Biology Zebrafish Cells Cultured 030304 developmental biology Pharmacology 0303 health sciences Mutation Extracellular Matrix Proteins Dose-Response Relationship Drug Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] Exons Oligonucleotides Antisense Zebrafish Proteins medicine.disease biology.organism_classification Molecular biology Exon skipping Disease Models Animal medicine.anatomical_structure 030220 oncology & carcinogenesis Commentary Molecular Medicine Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Retinitis Pigmentosa |
| Zdroj: | Molecular Therapy, 29, 8, pp. 2441-2455 Mol Ther Molecular Therapy, 29, 2441-2455 |
| ISSN: | 1525-0016 |
| Popis: | Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13. Skipping exon 13 from the USH2A transcript presents a potential treatment modality in which the resulting transcript is predicted to encode a slightly shortened usherin protein. Morpholino-induced skipping of ush2a exon 13 in zebrafish ush2(armc1) mutants resulted in the production of usherin Delta exon 13 protein and a completely restored retinal function. Antisense oligonucleotides were investigated for their potential to selectively induce human USH2A exon 13 skipping. Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation. Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection and induced a detectable level of exon skipping until at least 6 months post-injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13. |
| Databáze: | OpenAIRE |
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