The extensive molecular genetic heterogeneity seen with inherited eye disease is 
a major barrier to the development of gene-based therapeutics. The underlying 
molecular pathology in a considerable proportion of these diseases however are 
nonsense mutations leading to premature termination codons. A therapeutic 
intervention targeted at this abnormality would therefore potentially be 
relevant to a wide range of inherited eye diseases. We have taken advantage of 
the ability of aminoglycoside drugs to suppress such nonsense mutations and 
partially restore full-length, functional protein in a zebrafish model of 
choroideraemia (chm(ru848); juvenile chorio-retinal degeneration) and in two 
models of ocular coloboma (noi(tu29a) and gup(m189); congenital optic fissure 
closure defects). In vitro cell-based assays showed significant readthrough with 
two drugs, gentamicin and paromomycin, which was confirmed by western blot and 
in vitro prenylation assays. The presence of either aminoglycoside during 
zebrafish development in vivo showed remarkable prevention of mutant ocular 
phenotypes in each model and a reduction in multisystemic defects leading to a 
1.5-1.7-fold increase in survival. We also identified a significant reduction in 
abnormal cell death shown by TUNEL assay. To test the hypothesis that optic 
fissure closure was apoptosis-dependent, the anti-apoptotic agents, curcumin and 
zVAD-fmk, were tested in gup(m189) embryos. Both drugs were found to reduce the 
size of the coloboma, providing molecular evidence that cell death is required 
for optic fissure remodelling. These findings draw attention to the value of 
zebrafish models of eye disease as useful preclinical drug screening tools in 
studies to identify molecular mechanisms amenable to therapeutic intervention.