PUBLICATION
Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations
- Authors
- Dulla, K., Slijkerman, R., van Diepen, H.C., Albert, S., Dona, M., Beumer, W., Turunen, J.J., Chan, H.L., Schulkens, I.A., Vorthoren, L., Besten, C.D., Buil, L., Schmidt, I., Miao, J., Venselaar, H., Zang, J., Neuhauss, S.C.F., Peters, T., Broekman, S., Pennings, R., Kremer, H., Platenburg, G., Adamson, P., de Vrieze, E., van Wijk, E.
- ID
- ZDB-PUB-210428-9
- Date
- 2021
- Source
- Molecular therapy : the journal of the American Society of Gene Therapy 29(8): 2441-2455 (Journal)
- Registered Authors
- van Wijk, Erwin
- Keywords
- none
- MeSH Terms
-
- Animals
- Cells, Cultured
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Exons
- Extracellular Matrix Proteins/chemistry
- Extracellular Matrix Proteins/genetics
- Extracellular Matrix Proteins/metabolism*
- Humans
- Induced Pluripotent Stem Cells/cytology
- Induced Pluripotent Stem Cells/drug effects
- Induced Pluripotent Stem Cells/metabolism
- Mice
- Models, Molecular
- Mutation*
- Oligonucleotides, Antisense/administration & dosage*
- Oligonucleotides, Antisense/pharmacology
- Retina/metabolism
- Retinitis Pigmentosa/drug therapy*
- Retinitis Pigmentosa/genetics
- Retinitis Pigmentosa/metabolism
- Zebrafish
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 33895329 Full text @ Mol. Ther.
Citation
Dulla, K., Slijkerman, R., van Diepen, H.C., Albert, S., Dona, M., Beumer, W., Turunen, J.J., Chan, H.L., Schulkens, I.A., Vorthoren, L., Besten, C.D., Buil, L., Schmidt, I., Miao, J., Venselaar, H., Zang, J., Neuhauss, S.C.F., Peters, T., Broekman, S., Pennings, R., Kremer, H., Platenburg, G., Adamson, P., de Vrieze, E., van Wijk, E. (2021) Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Molecular therapy : the journal of the American Society of Gene Therapy. 29(8):2441-2455.
Abstract
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 of 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 ush2armc1 mutants resulted in the production of usherinΔexon 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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping