Long-Term Protection of Genetically Ablated Rabbit Retinal Degeneration by Sustained Transscleral Unoprostone Delivery.

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.

• Authors: Nobuhiro Nagai, Eri Koyanagi, Yasuko Izumida, Junjun Liu, Aya Katsuyama, Hirokazu Kaji, Matsuhiko Nishizawa, Noriko Osumi, Mineo Kondo, Hiroko Terasaki, Yukihiko Mashima, Toru Nakazawa, Toshiaki Abe
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 57 Issue 15 Pg. 6527-6538 (12 01 2016) ISSN: 1552-5783 [Electronic] United States
• PMID: 27918826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(3,5-dihydroxy-2-(oxodecyl)cyclopentyl)propionic acid
• Delayed-Action Preparations
• Drug Implants
• Large-Conductance Calcium-Activated Potassium Channels
• DNA
• Rhodopsin
• Dinoprost

Topics

• Animals
• Animals, Genetically Modified
• Aqueous Humor (metabolism)
• Choroid (metabolism, pathology)
• Chromatography, Liquid
• DNA (genetics)
• DNA Mutational Analysis
• Delayed-Action Preparations
• Dinoprost (administration & dosage, analogs & derivatives, pharmacokinetics)
• Disease Models, Animal
• Drug Implants
• Electroretinography
• Follow-Up Studies
• Gene Expression Regulation
• Immunohistochemistry
• In Situ Hybridization
• Large-Conductance Calcium-Activated Potassium Channels (biosynthesis, genetics)
• Mutation
• Rabbits
• Retina (metabolism, pathology, physiopathology)
• Retinal Degeneration (drug therapy, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Rhodopsin (biosynthesis, genetics)
• Sclera
• Time Factors
• Tomography, Optical Coherence