In vivo imaging reveals novel aspects of retinal disease progression in Rs1h(-/Y)  mice but no therapeutic effect of carbonic anhydrase inhibition.
OBJECTIVE
X-linked juvenile retinoschisis (XLRS) is the most common juvenile maculopathy in men and is caused by mutations in the gene encoding retinoschisin (RS1). Evidence in the literature on the therapeutic effect of carboanhydrase inhibitors (CAIs) to treat schisis formation in the retina has remained equivocal. Here, we evaluate the effect of the CAI dorzolamide on the structural and functional disease progression in the mouse model for XLRS (Rs1h(-/y)).


METHODS
Rs1h (-/y) mice were treated unilaterally with dorzolamide eye drops (Trusopt(®) 20 mg/mL) every 12 h for 2 weeks starting on postnatal day 14 (n = 27). Changes of retinal structure were monitored by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography 12 h, 14 days, 4 weeks, 2 months, and 6 months after completion of the treatment.


RESULTS
Schisis formation (peak at 3 months) preceded photoreceptor degeneration and hyper-fluorescence (peak at 7 months). Structural pathology was most severe in the superior hemi-retina with previously unreported hyper-fluorescent lesions. Quantitative analysis showed no significant differences regarding the inner or outer retinal thickness of the treated vs. untreated eyes 12 h after the completion of treatment (IRT(12 h) = -1.29 ± 1.89 μm; ORT(12 h) = 0.61 ± 2.08 μm; mean ± 95%CI) or at any later time point.


CONCLUSIONS
Time line analysis after short-term treatment with CAI failed to show short-, intermediate-, or long-term evidence of structural improvement in Rs1h(-/y) mice. Schisis formation in the inner retina peaked at the age of 3 months and was followed by photoreceptor degeneration predominantly in the superior hemi-retina. Previously unreported hyper-fluorescent lesions co-register with structural retinal pathologies.
Centre for Ophthalmology, University of Tübingen, Schleichstr, 12-16, 72076 Tübingen, Germany.
Ahmad
A
Zhour
Sylvia
S
Bolz
Christian
C
Grimm
Gabriel
G
Willmann
Andreas
A
Schatz
Bernhard H F
BH
Weber
Eberhart
E
Zrenner
M Dominik
MD
Fischer
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D051379:Mice; D009883:Ophthalmic Solutions; D012160:Retina / Q000187:drug effects / Q000473:pathology; D041441:Retinoschisis / Q000188:drug therapy / Q000473:pathology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*
D002257:Carbonic Anhydrase Inhibitors; D015815:Cell Adhesion Molecules; D005136:Eye Proteins; D009883:Ophthalmic Solutions; C491843:RS1 protein, mouse; D013449:Sulfonamides; D013876:Thiophenes; C062765:dorzolamide