Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 Disruption Using CRISPR-Cas9.
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.
['Wu|Jiahui|J|', 'Bell|Oliver H|OH|', 'Copland|David A|DA|', 'Young|Alison|A|', 'Pooley|John R|JR|', 'Maswood|Ryea|R|', 'Evans|Rachel S|RS|', 'Khaw|Peng Tee|PT|', 'Ali|Robin R|RR|', 'Dick|Andrew D|AD|', 'Chu|Colin J|CJ|']
D000818:Animals D051398:Aquaporin 1 D001483:Base Sequence D064113:CRISPR-Cas Systems D002924:Ciliary Body D000229:Dependovirus D000072669:Gene Editing D015870:Gene Expression D018390:Gene Targeting D015316:Genetic Therapy D005822:Genetic Vectors D005901:Glaucoma D051379:Mice D012160:Retina D014161:Transduction, Genetic D019076:Transgenes
Glaucoma ciliary body Aquaporin CRISPR-Cas9 intraocular pressure AAV gene editing