Long-Term Protection of Genetically Ablated Rabbit Retinal Degeneration by Sustained Transscleral Unoprostone Delivery.
Nagai Nobuhiro, Koyanagi Eri, Izumida Yasuko, Liu Junjun, Katsuyama Aya, Kaji Hirokazu, Nishizawa Matsuhiko, Osumi Noriko, Kondo Mineo, Terasaki Hiroko
AI Summary
Transscleral unoprostone delivery protected rabbit retinal function and structure for over 32 weeks, suggesting a promising long-term treatment for retinal degeneration like retinitis pigmentosa.
Abstract
Purpose
To evaluate the long-term protective effects of transscleral unoprostone (UNO) against retinal degeneration in transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation).
Methods
The UNO release devices (URDs) were implanted into the sclerae of Tg rabbits and ERG, optical coherence tomography (OCT), and ophthalmic examinations were conducted for 40 weeks. Unoprostone metabolites in retina, choroid/RPE, aqueous humor, and plasma from wild-type (Wt) rabbits were measured using liquid chromatography-tandem mass spectrometry. In situ hybridization and immunohistochemistry evaluated the retinal distribution of big potassium (BK) channels, and RT-PCR evaluated the expressions of BK channels and m-opsin at 1 week after URD treatment.
Results
The URD released UNO at a rate of 10.2 ±1.0 μg/d, and the release rate and amount of UNO decreased during 32 weeks. Higher ERG amplitudes were observed in the URD-treated Tg rabbits compared with the placebo-URD, or nontreated controls. At 24 weeks after implantation into the URD-treated Tg rabbits, OCT images showed preservation of retinal thickness, and histologic examinations (44 weeks) showed greater thickness of outer nuclear layers. Unoprostone was detected in the retina, choroid, and plasma of Wt rabbits. Retina/plasma ratio of UNO levels were 38.0 vs. 0.68 ng UNO*hour/mL in the URD-treated group versus control (topical UNO), respectively. Big potassium channels were observed in cone, cone ON-bipolar, and rod bipolar cells. Reverse-transcriptase PCR demonstrated BK channels and m-opsins increased in URD-treated eyes.
Conclusions
In Tg rabbits, URD use slowed the decline of retinal function for more than 32 weeks, and therefore provides a promising tool for long-term treatment of RP.
MeSH Terms
Shields Classification
Key Concepts6
The unoprostone release devices (URDs) released unoprostone at a rate of 10.2 1.0 g/d in transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation), with the release rate and amount of unoprostone decreasing during 32 weeks.
Higher ERG amplitudes were observed in the unoprostone release device (URD)-treated transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation) compared with the placebo-URD or nontreated controls, indicating long-term protective effects against retinal degeneration.
At 24 weeks after implantation into the unoprostone release device (URD)-treated transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation), optical coherence tomography (OCT) images showed preservation of retinal thickness, and histologic examinations (44 weeks) showed greater thickness of outer nuclear layers.
Unoprostone was detected in the retina, choroid, and plasma of wild-type (Wt) rabbits, with a retina/plasma ratio of unoprostone levels of 38.0 ng UNO*hour/mL in the unoprostone release device (URD)-treated group versus 0.68 ng UNO*hour/mL in the control (topical unoprostone) group.
Big potassium (BK) channels were observed in cone, cone ON-bipolar, and rod bipolar cells in wild-type (Wt) rabbits, and reverse-transcriptase PCR demonstrated BK channels and m-opsins increased in unoprostone release device (URD)-treated eyes.
In transgenic (Tg) rabbits (Pro347Leu rhodopsin mutation), unoprostone release device (URD) use slowed the decline of retinal function for more than 32 weeks, providing a promising tool for long-term treatment of retinitis pigmentosa (RP).
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