![]() ![]() RPE65 gene augmentation therapy and retinal prostheses have shown preliminary encouraging signs of visual rescue in early-stage clinical evaluations. LCA is incurable, but several possible therapies are being investigated. At or soon after birth, LCA patients characteristically exhibit severe visual impairment exhibited by wandering nystagmus, amaurotic pupils, a pigmentary retinopathy with loss of cone and rod sensitivity, absent or greatly attenuated electroretinographic (ERG) responses, and an approximately 100-fold decrease in cone flicker amplitudes. 4Two examples are Leber congenital amaurosis (LCA), a childhood-onset retinal disease causing severe visual impairment, and retinitis pigmentosa (RP), another retinopathy with a more variable age of onset. 3Defects in 11- cis-retinal production are associated with a number of inherited degenerative retinopathies. ![]() Regeneration of 11- cis-retinal completes this retinoid (visual) cycle and is critical for maintaining vision. 1 2The isomerized chromophore, all- trans-retinal, then is reduced to all- trans-retinol, transported to the retinal pigment epithelium (RPE), and converted to fatty acid all- trans-retinyl esters by lecithin/retinol acyltransferase (LRAT). Visual pigments, consisting of the chromophore 11- cis-retinal bound to apoprotein G protein-coupled receptor opsins, 1initiate this process on the absorption of a photon that triggers photoisomerization of the chromophore into its trans form. Visual perception results from the biological conversion of light energy to electrical signaling by retinal photoreceptors in the eye, a process called phototransduction. Treatment with 9- cis-R-Ac improves visual function and preserves retinal morphology in Rpe65 −/− mice. ![]() Treated mice also performed better than control animals in vision-dependent behavioral tests.Ĭonclusions. Mice given either daily or intermittent 9- cis-R-Ac treatment at 1 and 4 mg/kg and evaluated 8 weeks later displayed dose-dependent improvement of retinal function and morphology, whereas retinal function deteriorated in control animals. Significant dose-dependent improvement of electroretinographic responses was observed 6 days after administration of 9- cis-R-Ac daily for 3 days at 1 to 12.5 mg/kg. Well-tolerated daily doses (1–12.5 mg/kg) for 2 weeks induced remarkable improvement of retinal function. Single doses of 9- cis-R-Ac (6.25–50 mg/kg) provided significant dose-dependent improvement in electroretinographic responses. Soybean oil vehicle provided the highest 9- cis-R-Ac metabolite levels in plasma. Retinoid effects on visual function were evaluated by electroretinography, retinoid analyses, histologic methods, and vision-dependent behavioral testing. Then doses of 9- cis-R-Ac ranging from 1 to 100 mg/kg were administered to 5- to 12-week-old Rpe65 −/− mice by different treatment regimens, including single doses and either intermittent or daily doses for various periods up to 8 weeks. Young C57Bl/6 mice were given 9- cis-R-Ac in each of four different oil-based vehicle solutions by gastric gavage to identify the vehicle most suitable for drug delivery by measuring retinoid levels in plasma. Effects of 9- cis-retinyl acetate (9- cis-R-Ac) on visual function and retinopathy progression were tested in Rpe65 −/− mice. Mice lacking retinal pigment epithelium–specific 65-kDa protein (RPE65) develop retinopathy and blindness resembling Leber congenital amaurosis. ![]()
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