Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR-Cas9

Jiahui Wu, Oliver H. Bell, David A. Copland, Alison Young, John R. Pooley, Ryea Maswood, Rachel S. Evans, Peng Tee Khaw, Robin R. Ali, Andrew D. Dick, Colin J. Chu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)


Glaucoma is a common cause of blindness, yet current therapeutic options are imperfect. Clinical trials have invariably shown that reduction in intraocular pressure (IOP) regardless of disease subtype prevents visual loss. Reducing ciliary body aqueous humor production can lower IOP, and the adeno-associated virus ShH10 serotype was identified as able to transduce mouse ciliary body epithelium following intravitreal injection. Using ShH10 to deliver a single vector CRISPR-Cas9 system disrupting Aquaporin 1 resulted in reduced IOP in treated eyes (10.4 ± 2.4 mmHg) compared with control (13.2 ± 2.0 mmHg) or non-injected eyes (13.1 ± 2.8 mmHg; p < 0.001; n = 12). Editing in the aquaporin 1 gene could be detected in ciliary body, and no off-target increases in corneal or retinal thickness were identified. In experimental mouse models of corticosteroid and microbead-induced ocular hypertension, IOP could be reduced to prevent ganglion cell loss (32 ± 4 /mm2) compared with untreated eyes (25 ± 5/mm2; p < 0.01). ShH10 could transduce human ciliary body from post-mortem donor eyes in ex vivo culture with indel formation detectable in the Aquaporin 1 locus. Clinical translation of this approach to patients with glaucoma may permit long-term reduction of IOP following a single injection.

Original languageEnglish
Pages (from-to)820-829
Number of pages10
JournalMolecular Therapy
Issue number3
Publication statusPublished - 4 Mar 2020


  • AAV
  • Aquaporin
  • ciliary body
  • CRISPR-Cas9
  • gene editing
  • Glaucoma
  • intraocular pressure


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