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D. Bok, M. Levine, D. Zack, S. Nusinowitz; Partial Rescue of Retinal Structure and Function in Rds-/- Mice With an Inducible Rds Minigene . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1077.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the window of opportunity for gene replacement therapy in the rds-/- mouse, a model for retinitis pigmentosa. Methods: Rds-/- mice carrying IRBP and rod opsin promoter-driven transgenes for the reverse tetracycline transactivator (rtTA) and an rds transgene driven by the tetracycline response element were the subject of this study. The animals were given doxycycline (Dox) in their drinking water at the time that they were weaned (P17) and treatment with Dox was then continued for various periods of time. Retinal function was evaluated with the electroretinogram (ERG) recorded at 1 and 2 months after beginning treatment at 20 mg/ml of Dox. Rod-mediated b-waves were fitted with a Naka-Rushton function to estimate the maximum saturated amplitude (Vmax) and the semisaturation intensity. Rod a-waves were fitted with a rod model to estimate RmP3, the saturated a-wave amplitude, and S, a sensitivity parameter. Retinal morphology was analyzed as a function of treatment. Results: After 1 month of treatment, ERGs from untreated controls were minimally detectable. In contrast, ERGs from treated littermates were well-defined with Vmax amplitudes of 181.3 ± 14.7 µV. Vmax obtained from rds+/- nontransgenic controls was 429.8 ± 68 µV. The semi-saturation intensity was modestly elevated in treated mice. Whorl-shaped photoreceptor outer segments similar to those observed in rds+/- controls were observed in rds-/- transgenic animals. Physiological rescue persisted during two months of treatment in rds-/- transgenic animals whereas ERGs from untreated controls were non-detectable. In addition, the a-wave analysis at 2 months revealed a significantly reduced RmP3, but a normal S, indicating that phototransduction kinetics were within normal limits for the rds-/- transgenic animals. Conclusions: The results offer hope for persistence of function as a consequence of gene therapy, at least when presented in an optimized setting in which panretinal induction of a rescue transgene is achieved. We are currently analyzing the postnatal age of animals at which rescue can no longer be effected.
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