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- Author or Editor: Brian C. Gilger x
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ABSTRACT
This review, which is part of the “Currents in One Health” series, describes the importance of the study of immune-mediated ocular disease in the development of innovative therapeutics, such as cell and gene therapy for the eye. Recent examples of cell and gene therapy studies from the author’s laboratory are reviewed to emphasize the importance of One Health initiatives in developing innovative therapies for ocular diseases. Spontaneous immune-mediated corneal disease is common in horses, cats, dogs, and humans. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) injected subconjunctivally resulted in the resolution of naturally occurring immune-mediated keratitis (IMMK) without adverse effects. These results support that autologous subconjunctival BM-MSC therapy may be a viable treatment alternative for IMMK. Furthermore, the use of subconjunctival MSCs may be an effective method to treat ocular surface immune-mediated diseases in humans and other species, including herpetic stromal keratitis and immunologic dry eye disease. Furthermore, the use of adeno-associated viral (AAV) vectors to deliver the immunosuppressive transgene cDNA of equine interleukin 10 (eqIL-10) or human leukocyte antigen G injected intravitreally was shown to be safe and inhibited the development of uveitis in the experimental autoimmune uveitis rat model. Efficacy and safety studies of ocular gene therapy in models will pave the way for clinical trials in animals with naturally occurring immune-mediated diseases, such as a therapeutic clinical trial for AAV-eqIL-10 in horses with equine recurrent uveitis.
Abstract
In this article, which is part of the Currents in One Health series, the role of naturally occurring ocular disease in animals is reviewed with emphasis on how the understanding of these ocular diseases contributes to one health initiatives, particularly the pathogenesis and treatment of ocular diseases common to animals and humans. Animals spontaneously develop ocular diseases that closely mimic those in humans, especially dry eye disease, herpes virus infection (cats), fungal keratitis (horses), bacterial keratoconjunctivitis, uveitis, and glaucoma. Both uveitis and glaucoma are common in domestic animals and humans, and many similarities exist in pathogenesis, genetics, and response to therapy. Furthermore, the study of inherited retinal disease in animals has particularly epitomized the one health concept, specifically the collaborative efforts of multiple disciplines working to attain optimal health for people and animals. Through this study of retinal disease in dogs, innovative therapies such as gene therapy have been developed. A unique opportunity exists to study ocular disease in shared environments to better understand the interplay between the environment, genetics, and ocular disease in both animals and humans. The companion Currents in One Health by Gilger, AJVR, December 2022, addresses in more detail recent studies of noninfectious immune-mediated animal ocular disease and their role in advancing ocular health globally.
Abstract
Objective—To evaluate the outcome of thermokeratoplasty for treatment of ulcerative keratitis and bullous keratopathy secondary to corneal endothelial disease in dogs.
Design—Retrospective study.
Animals—13 dogs.
Procedures—Medical records from 1994 to 2001 for dogs evaluated because of ulcerative keratitis and bullous keratopathy and treated with thermokeratoplasty were reviewed.
Results—There were 7 spayed females, 5 castrated males, and 1 sexually intact male, ranging from 6 to 16 years of age. Ten dogs had endothelial degeneration, and 3 dogs had breed-related endothelial dystrophy. All dogs had bullous keratopathy, characterized by microbullae formation that was detected via biomicroscopy. Recurrent or nonhealing corneal ulcers were detected unilaterally in 5 dogs and bilaterally in 8 dogs. Mean ± SD duration from thermokeratoplasty until ulcerations were healed for all dogs was 2.2 ± 1.1 weeks. All dogs that underwent thermokeratoplasty for nonhealing corneal ulceration secondary to endothelial disease and corneal edema had epithelial wound healing and resolution of corneal ulceration. Mean duration of treatment (ie, topical treatment required until resolution of ulceration) was significantly less after thermokeratoplasty than duration of treatment (with multiple treatments) prior to referral.
Conclusions and Clinical Relevance—It may be necessary to perform thermokeratoplasty of the entire cornea to prevent recurrence of ulcerations in areas that have not been treated with thermokeratoplasty. (J Am Vet Med Assoc 2003;222: 607–612)
Abstract
Objective—To evaluate the use of an intravitreal sustained-release cyclosporine (CsA) delivery device for treatment of horses with naturally occurring recurrent uveitis.
Animals—16 horses with recurrent uveitis.
Procedures—Horses with frequent recurrent episodes of uveitis or with disease that was progressing despite appropriate medication were selected for this study. Additional inclusion criteria included adequate retinal function as determined by use of electroretinography, lack of severe cataract formation, and no vision-threatening ocular complications (eg, retinal detachment, severe retinal degeneration, and posterior synechia). Sustained-release CsA delivery devices (4 µg of CsA/d) were implanted into the vitreous through a sclerotomy at the pars plana. Reexaminations were performed 1, 3, 6, and 12 months after implantation, then continued annually. Ophthalmic changes, number of recurrent episodes of uveitis, and vision were recorded.
Results—The rate of recurrent episodes after device implantation (0.36 episodes/y) was less than prior to surgery (7.5 episodes/y). In addition, only 3 horses developed episodes of recurrent uveitis after surgery. Vision was detected in 14 of 16 affected eyes at a mean follow-up time of 13.8 months (range, 6 to 24 months).
Conclusions and Clinical Relevance—This intravitreal sustained-release CsA delivery device may be a safe and important tool for long-term treatment of horses with chronic recurrent uveitis. (Am J Vet Res 2001;62:1892–1896)
Abstract
Objective—To characterize clinical and clinicopathologic findings, response to treatment, and causes of systemic hypertension in cats with hypertensive retinopathy.
Design—Retrospective study.
Animals—69 cats with hypertensive retinopathy.
Procedure—Medical records from cats with systemic hypertension and hypertensive retinopathy were reviewed.
Results—Most cats (68.1%) were referred because of vision loss; retinal detachment, hemorrhage, edema, and degeneration were common findings. Cardiac abnormalities were detected in 37 cats, and neurologic signs were detected in 20 cats. Hypertension was diagnosed concurrently with chronic renal failure (n = 22), hyperthyroidism (5), diabetes mellitus (2), and hyperaldosteronism (1). A clearly identifiable cause for hypertension was not detected in 38 cats; 26 of these cats had mild azotemia, and 12 did not have renal abnormalities. Amlodipine decreased blood pressure in 31 of 32 cats and improved ocular signs in 18 of 26 cats.
Conclusions and Clinical Relevance—Retinal lesions, caused predominantly by choroidal injury, are common in cats with hypertension. Primary hypertension in cats may be more common than currently recognized. Hypertension should be considered in older cats with acute onset of blindness; retinal edema, hemorrhage, or detachment; cardiac disease; or neurologic abnormalities. Cats with hypertensioninduced ocular disease should be evaluated for renal failure, hyperthyroidism, diabetes mellitus, and cardiac abnormalities. Blood pressure measurements and funduscopic evaluations should be performed routinely in cats at risk for hypertension (preexisting renal disease, hyperthyroidism, and age > 10 years). Amlodipine is an effective antihypertensive agent in cats.(J Am Vet Med Assoc 2000;217:695–702)
Abstract
Objective—To determine penetration of topically and orally administered voriconazole into ocular tissues and evaluate concentrations of the drug in blood and signs of toxicosis after topical application in horses.
Animals—11 healthy adult horses.
Procedure—Each eye in 6 horses was treated with a single concentration (0.5%, 1.0%, or 3.0%) of a topically administered voriconazole solution every 4 hours for 7 doses. Anterior chamber paracentesis was performed and plasma samples were collected after application of the final dose. Voriconazole concentrations in aqueous humor (AH) and plasma were measured via high-performance liquid chromatography. Five horses received a single orally administered dose of voriconazole (4 mg/kg); anterior chamber paracentesis was performed, and voriconazole concentrations in AH were measured.
Results—Mean ± SD voriconazole concentrations in AH after topical administration of 0.5%, 1.0%, and 3.0% solutions (n = 4 eyes for each concentration) were 1.43 ± 0.37 μg/mL, 2.35 ± 0.78 μg/mL, and 2.40 ± 0.29 μg/mL, respectively. The 1.0% and 3.0% solutions resulted in significantly higher AH concentrations than the 0.5% solution, and only the 3.0% solution induced signs of ocular toxicosis. Voriconazole was detected in the plasma for 1 hour after the final topically administered dose of all solutions. Mean ± SD voriconazole concentration in AH after a single orally administered dose was 0.86 ± 0.22 μg/mL.
Conclusions and Clinical Relevance—Results indicated that voriconazole effectively penetrated the cornea in clinically normal eyes and reached detectable concentrations in the AH after topical administration. The drug also penetrated noninflamed equine eyes after oral administration. Low plasma concentrations of voriconazole were detected after topical administration.
Abstract
Objective—To evaluate the anterior chamber approach and energy levels for endoscopic cyclophotocoagulation (ECPC) and assess ECPC-induced tissue damage in phakic eyes of bovine cadavers.
Sample—12 bovine cadaver eyes.
Procedures—Angle of reach was measured in 6 eyes following placement of a curved endoscopic probe through multiple corneal incisions. In another 6 eyes, each ocular quadrant underwent ECPC at 1 of 3 energy levels (0.75, 0.90, and 1.05 J) or remained untreated. Visible effects on tissues (whitening and contraction of ciliary processes) were scored (scale of 0 [no effects] to 6 [severe effects]), and severity and extent of histologic damage to the pigmented and nonpigmented ciliary epithelium and fibromuscular stroma were each scored (scale of 0 [no effect] to 3 [severe effect]) and summed for each quadrant. Overall mean scores for 6 quadrants/treatment were calculated.
Results—Mean ± SD combined angle of reach was 148 ± 24° (range, 123 ± 23° [ventromedial] to 174 ± 11° [dorsolateral]). At the 0.75-, 0.90-, and 1.05-J levels, mean visible tissue effect scores were 3.12 ± 0.47, 3.86 ± 0.35, and 4.68 ± 0.58, respectively; mean histologic damage scores were 4.79 ± 1.38 (mild damage), 6.82 ± 1.47 (moderate damage), and 9.37 ± 1.42 (severe damage), respectively. Occasional popping noises (venting of vaporized interstitial water) were heard at the 1.05-J level.
Conclusions and Clinical Relevance—Multiple incisions were necessary to facilitate 360° ECPC treatment in bovine eyes. For ECPC in vivo, the 0.75- and 0.90-J energy levels had the potential to effectively treat the ciliary epithelium.
Abstract
Objective—To determine appropriate intraocular lens (IOL) implant strength to approximate emmetropia in horses.
Sample Population—16 enucleated globes and 4 adult horses.
Procedures—Lens diameter of 10 enucleated globes was measured. Results were used to determine the appropriate-sized IOL implant for insertion in 6 enucleated globes and 4 eyes of adult horses. Streak retinoscopy and ocular ultrasonography were performed before and after insertion of 30-diopter (D) IOL implants (enucleated globes) and insertion of 25-D IOL implants (adult horses).
Results—In enucleated globes, mean ± SD lens diameter was 20.14 ± 0.75 mm. Preoperative and postoperative refractive state of enucleated globes with 30-D IOL implants was −0.46 ± 1.03 D and −2.47 ± 1.03 D, respectively; preoperative and postoperative difference in refraction was 2.96 ± 0.84 D. Preoperative anterior chamber (AC) depth, crystalline lens thickness (CLT), and axial globe length (AxL) were 712 ± 0.82 mm, 11.32 ± 0.81 mm, and 40.52 ± 1.26 mm, respectively; postoperative AC depth was 10.76 ± 1.16 mm. Mean ratio of preoperative to postoperative AC depth was 0.68. In eyes receiving 25-D IOL implants, preoperative and postoperative mean refractive error was 0.08 ± 0.68 D and −3.94 ± 1.88 D, respectively. Preoperative AC depth, CLT, and AxL were 6.36 ± 0.22 mm, 10.92 ± 1.92 mm, and 38.64 ± 2.59 mm, respectively. Postoperative AC depth was 8.99 ± 1.68 mm. Mean ratio of preoperative to postoperative AC depth was 0.73.
Conclusions and Clinical Relevance—Insertion of 30-D (enucleated globes) and 25-D IOL implants (adult horses) resulted in overcorrection of refractive error.
