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P. Bast, E. Filippova, N. Khan, B. Chang, N.L. Hawes, J.R. Heckenlively; Effect of Gentamicin Therapy on Retinal Function in Rd12 and Nclf Mutant Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1060.
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© ARVO (1962-2015); The Authors (2016-present)
Gentamicin, an aminoglycoside antibiotic, has the putative ability to induce readthrough of stop–codon mutations and produce functional improvement in nonsense mutation–mediated disease processes such as cystic fibrosis and muscular dystrophy. In this study, we attempt to improve retinal function with gentamicin therapy in two nonsense mutation mouse models of human retinal degenerative disease: retinal degeneration 12 (Rpe65rd12) and neuronal ceroid lipofuscinosis (Cln6nclf).
Mouse pups in each strain were divided into untreated and treated groups at birth. Treated pups received gentamicin via mother’s drinking water (300µg/ml) until weaning. Upon weaning, treated pups were divided into groups receiving a daily 34µg/g gentamicin injection, a daily 68µg/g gentamicin injection, or gentamicin–fortified water at 300µg/ml or 600µg/ml, respectively. ERGs were recorded in untreated and treated groups at weaning (3 weeks of age), 7 weeks of age, and 11 weeks of age. Eye tissue was obtained for histologic analysis at 11 weeks of age.
ERG analysis revealed a transient improvement in retinal function in treated rd12 animals compared to untreated rd12 mice. At 3 weeks of age, scotopic B–wave response was improved in treated animals compared to controls (8.34µV ± 4.9 vs. 5.37µV ± 3.55, p=0.022), as was dark–adapted bright flash response (46.6µV ± 24.5 vs. 24.3µV ± 10.3, p<0.003) and photopic response (43.8µV ± 21.4 vs. 29.3µV ± 13.6, p=0.0067). At 7 weeks of age only the photopic B–wave response was improved in rd12 animals treated with daily gentamicin injections of 34µg/g (13.6µV ± 4.2 vs. 8.3µV ± 4.0, p=0.029). At 11 weeks the scotopic response was improved in 68µg/g treatment group (5.5µV ± 4.1 vs. 2.4µV ± 1.0, p=0.04), while the dark adapted bright flash response was worsened in the 34µg/g treatment group (7.0µV ± 2.7 vs. 12.9µV ± 5.3, p=0.007). Treated nclf mice showed a mixed ERG response at 3 weeks compared to untreated nclf mice, with no difference in scotopic B–wave response, worsened dark–adapted bright flash response (75.3µV ± 24.7 vs. 134.1µV ± 26.9, p<0.003), and improved photopic response (59.8µV ± 12.1 vs. 39.7µV ± 10.5, p<0.003). No significant differences in ERG response between groups were found at 7 or 11 weeks of age.
Gentamicin appears to have mixed results as a potential therapy for nonsense mutation–induced retinal degenerative disease in the two models we tested, and other aminoglycosides and mouse strains need investigation.
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