@article{crabtree_uribe_smith_roberts_salmon_bower_song_bastola_hirsch_gilger_2022, title={Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy}, volume={17}, ISSN={["1932-6203"]}, url={https://doi.org/10.1371/journal.pone.0270972}, DOI={10.1371/journal.pone.0270972}, abstractNote={Equine recurrent uveitis (ERU) is a spontaneous, painful, and vision threatening disease affecting up to 25% of equine populations worldwide. Current treatments of ERU are non-specific and have many side effects which limits them to short-term use. In order to develop an effective therapy for ERU, we investigated the use of adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by equine interleukin-10 (Equine-IL10). The purpose of this study was to evaluate the therapeutic efficacy of a single intravitreal (IVT) dose of AAV8-Equine-IL10 gene therapy for inhibition of experimental autoimmune uveitis (EAU) in rats. Each rat was dosed intravitreally (IVT) in both eyes with either balanced salt solution (BSS) (control; n = 4), AAV8-Equine-IL10 at a low dose (2.4x109 vg; n = 5) or high dose (2.4x1010 vg; n = 5). EAU was induced in all groups of rats 7 days after IVT injections and euthanized 21 days post-injection. Ophthalmic examination and aqueous humor (AH) cell counts were recorded with the observer blinded to the treatment groups. Histopathology and qPCR were performed on selected ocular tissues. Data presented herein demonstrate that AAV8-Equine-IL10 treated rats exhibited a significant decrease in clinical inflammatory scores and AH cell counts compared to BSS-treated EAU eyes on days 10, 12 and 14 post EAU induction at both administered vector doses. Mean cellular histologic infiltrative scores were also significantly less in AAV8-Equine-IL10 dosed rats compared to the BSS group. Intravitreal injection of AAV8-Equine-IL10 resulted in Equine-IL10 cDNA expression in the ciliary body, retina, cornea, and optic nerve in a dose-dependent manner. A single IVT injection of AAV8-Equine-IL10 appeared to be well-tolerated and inhibited EAU even at the lowest administered dose. These results demonstrate safety and efficacy of AAV8-Equine-IL10 to prevent EAU and support continued exploration of AAV gene therapy for the treatment of equine and perhaps human recurrent uveitis.}, number={8}, journal={PLOS ONE}, author={Crabtree, Elizabeth and Uribe, Katy and Smith, Sara M. and Roberts, Darby and Salmon, Jacklyn H. and Bower, Jacquelyn J. and Song, Liujiang and Bastola, Prabhakar and Hirsch, Matthew L. and Gilger, Brian C.}, editor={Taylor, Andrew W.Editor}, year={2022}, month={Aug} }
 @article{smith_salmon_abbaraju_amin_gilger_2021, title={Tolerability, pharmacokinetics, and pharmacodynamics of a brinzolamide episcleral sustained release implant in normotensive New Zealand white rabbits}, volume={61}, ISSN={1773-2247}, url={http://dx.doi.org/10.1016/j.jddst.2020.102123}, DOI={10.1016/j.jddst.2020.102123}, abstractNote={Although episcleral drug delivery is a practical and minimally invasive method for sustained release ocular therapeutics, many polymer drug delivery systems induce ocular inflammation and have variable duration of drug release limiting their clinical use. The purpose of this study was to evaluate the in vitro release, tolerability, ocular drug distribution, and pharmacodynamics of brinzolamide released from episcleral silicone matrix devices. In vitro release of low-dose (12 mm × 2 mm; 7.5 mg total drug) and high-dose (20 mm × 2 mm; 12 mg total drug) silicone matrix implants (30% brinzolamide by weight) for 63 days was measured by high-performance liquid chromatography. New Zealand White (NZW) rabbits had either a blank silicone implant (n = 2 eyes), or a low or high-dose brinzolamide implant placed episclerally (n = 8 eyes each). Ocular inflammatory scoring and intraocular pressure (IOP) was measured at 0, 1–7, 10, 14, 21, and 28 days after implantation. Tissues were collected at either day 7 or 28 post implantation for histopathology and aqueous and vitreous humor drug analysis. In vitro release of brinzolamide revealed an initial burst of drug followed by a steady sustained release, with an estimated >12-month release profile. Both high and low-dose implants were well tolerated in NZW rabbits with minimal conjunctival hyperemia that resolved day 21. Eyes with brinzolamide implants had approximately 15–20% sustained reduction of IOP through day 28 after implantation compared to placebo implant eyes. Histopathology revealed mild focal mononuclear cellular infiltrates and fibrosis around the implant site at day 7 and day 28, but no evidence of intraocular toxicity. Brinzolamide was detected in the vitreous humor in a dose and time dependent manner. Episcleral brinzolamide-loaded silicone-matrix implants were extremely well tolerated and delivered sustained drug levels and therapeutic effect for up to 28 days in a rabbit model with an estimated duration of delivery of greater than 12 months.}, journal={Journal of Drug Delivery Science and Technology}, publisher={Elsevier BV}, author={Smith, Sara M. and Salmon, Jacklyn H. and Abbaraju, Santhi and Amin, Rasid and Gilger, Brian C.}, year={2021}, month={Feb}, pages={102123} }
 @article{hirsch_conatser_smith_salmon_wu_buglak_davis_gilger_2017, title={AAV vector-meditated expression of HLA-G reduces injury-induced corneal vascularization, immune cell infiltration, and fibrosis}, volume={7}, ISSN={2045-2322}, url={http://dx.doi.org/10.1038/s41598-017-18002-9}, DOI={10.1038/s41598-017-18002-9}, abstractNote={Abstract Over 1.5 million individuals suffer from cornea vascularization due to genetic and/or environmental factors, compromising visual acuity and often resulting in blindness. Current treatments of corneal vascularization are limited in efficacy and elicit undesirable effects including, ironically, vision loss. To develop a safe and effective therapy for corneal vascularization, adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by human leukocyte antigen G (HLA-G), was investigated. Self-complementary AAV cassettes containing codon optimized HLA-G1 (transmembrane) or HLA-G5 (soluble) isoforms were validated in vitro . Then, following a corneal intrastromal injection, AAV vector transduction kinetics, using a chimeric AAV capsid, were determined in rabbits. One week following corneal trauma, a single intrastromal injection of scAAV8G9-optHLA-G1 + G5 prevented corneal vascularization, inhibited trauma-induced T-lymphocyte infiltration (some of which were CD8 + ), and dramatically reduced myofibroblast formation compared to control treated eyes. Biodistribution analyses suggested AAV vectors persisted only in the trauma-induced corneas; however, a neutralizing antibody response to the vector capsid was observed inconsistently. The collective data demonstrate the clinical potential of scAAV8G9-optHLA-G to safely and effectively treat corneal vascularization and inhibit fibrosis while alluding to broader roles in ocular surface immunity and allogenic organ transplantation.}, number={1}, journal={Scientific Reports}, publisher={Springer Nature}, author={Hirsch, Matthew L. and Conatser, Laura M. and Smith, Sara M. and Salmon, Jacklyn H. and Wu, Jerry and Buglak, Nicholas E. and Davis, Rich and Gilger, Brian C.}, year={2017}, month={Dec} }
 @article{smith_westermeyer_mariani_gilger_davidson_2017, title={Optic neuritis in dogs: 96 cases (1983-2016)}, volume={21}, ISSN={1463-5216}, url={http://dx.doi.org/10.1111/vop.12528}, DOI={10.1111/vop.12528}, abstractNote={OBJECTIVE
To characterize ocular and neurologic findings, causes, and treatment outcomes of dogs with optic neuritis.


PROCEDURE
Medical records from dogs with a diagnosis of optic neuritis at North Carolina State University, College of Veterinary Medicine, Veterinary Hospital between 1983 and 2016 were reviewed.


RESULTS
Ninety-six cases (20 unilateral, 76 bilateral), comprised of 38 males and 58 females with a mean age of 6.1 ± 3.0 years (range 0.5-13), were identified. Seventy-four cases were presented for vision loss, and 42 had other concurrent neurologic abnormalities. Funduscopic findings included optic nerve head elevation (n = 92), peripapillary retinal edema or separation (n = 37), retinal hemorrhage or dilation of retinal vasculature (n = 23), and multiple inflammatory foci in the peripapillary region (n = 13). Retrobulbar optic neuritis was diagnosed in four cases. The final diagnoses included the following: multifocal meningoencephalitis of unknown etiology (MUE, n = 35), isolated optic neuritis (I-ON, n = 42), neoplasia (n = 10), microbial infection (n = 6), orbital inflammation (n = 2), and suspected ivermectin toxicosis (n = 1). Dogs with I-ON were more commonly male, and medium-to-large breed, when compared to dogs with MUE. Follow-up was available in 72 cases, 50 of which remained blind, 10 had partial visual improvement, and 12 were assessed as having normal vision in the affected eye(s).


CONCLUSION
Optic neuritis was most commonly associated with multifocal MUE or was isolated as the sole neurologic finding, with a similar incidence between the two groups. Findings suggest that a clinical syndrome of isolated optic neuritis, distinct from multifocal MUE, occurs in dogs.}, number={5}, journal={Veterinary Ophthalmology}, publisher={Wiley}, author={Smith, Sara M. and Westermeyer, Hans D. and Mariani, Christopher L. and Gilger, Brian C. and Davidson, Michael G.}, year={2017}, month={Dec}, pages={442–451} }