Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations

被引：102

作者：

Dulla, Kalyan ^{[1
]}

Slijkerman, Ralph ^{[2
]}

van Diepen, Hester C. ^{[1
]}

Albert, Silvia ^{[3
]}

Dona, Margo ^{[2
]}

Beumer, Wouter ^{[1
]}

Turunen, Janne J. ^{[1
]}

Chan, Hee Lam ^{[1
]}

Schulkens, Iris A. ^{[1
]}

Vorthoren, Lars ^{[1
]}

den Besten, Cathaline ^{[1
]}

Buil, Levi ^{[1
]}

Schmidt, Iris ^{[1
]}

Miao, Jiayi ^{[1
]}

Venselaar, Hanka ^{[4
]}

Zang, Jingjing ^{[5
]}

Neuhauss, Stephan C. F. ^{[5
]}

Peters, Theo ^{[2
]}

Broekman, Sanne ^{[2
]}

Pennings, Ronald ^{[2
]}

Kremer, Hannie ^{[2
,3
]}

Platenburg, Gerard ^{[1
]}

Adamson, Peter ^{[1
,6
]}

de Vrieze, Erik ^{[2
]}

van Wijk, Erwin ^{[2
]}

机构：

[1] ProQR Therapeut, Zernikedreef 9, NL-2333 CK Leiden, Netherlands

[2] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Otorhinolaryngol, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Human Genet, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Ctr Mol & Biomol Informat, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[5] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland

[6] UCL, Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England

来源：

MOLECULAR THERAPY | 2021年 / 29卷 / 08期

关键词：

SYNDROME TYPE IIA; MESSENGER-RNA; HEARING; GENE; PHOTORECEPTORS; ZEBRAFISH; USHERIN; LAMININ; SAFETY; NOTCH3;

D O I：

10.1016/j.ymthe.2021.04.024

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：2441 / 2455

页数：15

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