Mitigation of Equine Recurrent Uveitis Through Topical Suppressor of Cytokine Signaling-1 Mimetic Peptide: Open Label Safety and E cacy Pilot Study

Caryn E Plummer University of Florida Timothy Polk University of Florida Jatin Sharma University of Florida Sarah Bae University of Florida Olivia Barr University of Florida Amari Jones University of Florida Holly Kitchen University of Florida Michelle Wilhelmy University of Florida K Devin University of Florida Wesley Clay Smith University of Florida Bryan D. Kolaczkowski University of Florida Joseph Larkin (  jlarkin3@u .edu ) University of Florida


Introduction
Uveitis is a collection of sight-threatening intraocular diseases that are driven by aberrant in ammation from the immune system. Recurrent uveitis is characterized by repeated relapse (acute disease) and "remission" cycles of intraocular in ammation. In addition to relapse/remission cycles, some patients experience insidious disease where chronic subclinical disease drives ocular decrements. Equine recurrent uveitis (ERU) is a major cause of equine blindness and euthanasia affecting 10-25% of the horse population 1,2 . As such, a critical unmet need remains for ERU despite the e cacy of standard care, which includes the administration of topical steroids 3 . The reoccurring nature of the disease often results in patients becoming refractory to traditional therapy. Additionally, the prolonged use of steroids can produce many undesirable side effects, such as corneal disease (band keratopathy, delayed healing of corneal ulcerations and local immunosuppression) and predisposition to infection thus potentiating risks associated with daily use of steroids to alleviate in ammation.
ERU is also the only known spontaneous model of human recurrent uveitis, which is a leading cause of ocular detriment within human patients. Uveitis accounts for 30,000 new cases of human blindness in the US per year and is responsible for 3-10% of all blindness worldwide 4 . ERU and recurrent human uveitis are autoimmune diseases driven by heavy in ux of T lymphocytes into the uveal tract (which includes the iris, choroid, and stroma of the ciliary body) that produce high levels of destructive proin ammatory cytokines. Th1 (interferon gamma) and Th17 (interleukin (IL-6), IL23, IL17) phenotypes are present within the in ltrate and are thought to co-contribute to disease progression [5][6][7][8][9] . Indeed, IL6mediated necrosis of non-pigmented ciliary tissues is a common presentation in ERU. The in ux of T cells (speci c for ocular antigens) results in hypopyon (leukocytic exudate), photophobia, and edema 1 .
As such, novel strategies to inhibit pro-in ammatory cytokine signaling, or T lymphocyte in ltration, would likely improve current standard of care for uveitis patients.
Although in ammation is essential for the elimination of pathogens and cancers, it must be regulated to prevent destruction of self-tissues. SOCS1, also known as STAT induced-STAT inhibitor 1, is an intracellular protein that regulates in ammation by limiting cellular responsiveness to cytokines 10 . SOCS1 operates in a classical feedback inhibition manner, in which SOCS1 protein is induced by a cytokine to limit the pro-in ammatory cascade mediated by that cytokine. SOCS1 is present in hematopoietic and non-hematopoietic cells and is highly conserved between vertebrate species, including humans, rodents, and horses. 11 SOCS1 is a potent regulator of several cytokines, including interferon gamma and IL6. SOCS1 possesses two well established mechanisms for the regulation of cytokine signaling: 1) a SOCS box, which targets intracellular proteins involved in the proin ammatory cascade to proteasomal degradation and 2) a kinase inhibitory region (KIR) that inhibits the function of kinases (mal and Jak2) involved in promoting the in ammatory signal. Mice de cient in SOCS1 (SOCS1-/-) die of a perinatal auto-in ammatory disease. In addition, SOCS1 de ciencies have been implicated within lupus, scleritis, multiple sclerosis, and asthma patients [12][13][14][15] indicating that strategies that restore SOCS1 function may have e cacy in autoimmunity/autoin ammation. 16 We have previously shown that peritoneal administration of a peptide mimic of SOCS1, SOCS1-KIR, inhibited progression of experimental autoimmune encephalomyelitis (a rodent model of multiple sclerosis), rescued SOCS1-/-mice from perinatal lethality, and reduced lupus pathologies in preclinical models [17][18][19] . In addition, we have shown that the topical application of SOCS1-KIR peptide in a simple eye drop form mitigated experimentally induced uveitis in mice and rats 3,20 . In this study using rodents, the topical administration of the peptide was demonstrated to be both safe and effective. Current standard of care strategies for the treatment of recurrent uveitis (RU) are e cacious in most cases, however there is still an unmet need as unresponsive cases of RU are a leading cause of ocular morbidity in horses and humans. This pilot study tests the potential to translate previous studies, showing mitigation of induced experimental rodent uveitis, to spontaneous ERU clinical disease. In this study we demonstrate the high putative homology of the SOCS1-KIR mimetic peptide to the equine SOCS1 and putative binding of the SOCS-KIR mimetic peptide to the equine JAK2 protein. In addition, we show that topical administration of SOCS1-KIR was safe to the equine eye and was signi cantly correlated to reduced ERU-associated discomfort, hyperemia, and aqueous are. Together these results of this pilot study justify more detailed analysis of the use of the SOCS1 mimetic as a novel therapeutic treatment for ERU.

Conservation and Phylogeny of SOCS1 KIR
The amino acid sequences for SOCS1 from 10 different vertebrate species were retrieved from National Center for Biotechnology Information's (NCBI's) protein database. 21 Of the 10 amino acid sequences, 6 were from mammals (Homo sapiens, Rattus norvegicus, Mus musculus, Equus caballus, Bos taurus, Pan troglodytes), 1 was from a bird (Gallus gallus), 1 was from a reptile (Terrapene carolina), 1 was from an amphibian (Xenopus laevis), and 1 was from a sh (Danio rerio). The 10 sequences were aligned using Rhône-Alpes Bioinformatics Center's MULTALIN software. 22 Following the alignment, the sequences were exported to JalView 23,24 . In JalView, the aligned sequences were trimmed, leaving only the KIR domain. The KIR domain was then colored using the ClustalX coloring scheme. A logo of the trimmed KIR alignment was generated using the University of California Berkeley's Web Logo tool. 25 The original SOCS1 protein sequences and the trimmed SOCS1 KIR sequences were imported into phylogeny.fr. 26 The default settings were used to generate two phylogenetic trees. The trees were exported in Newick format and annotated in FigTree v1. 4.4. 27 In silico Modelling of SOCS1 KIR and JAK2 Structural models of horse JAK2 (ENSECAP00000008048) bound to horse SOCS1 (ENSECAP00000022763) or the SOCS1 KIR peptide were constructed using MODELLER v9.23. 28 The structure of human JAK1 bound to human SOCS1 (6C7Y) was used as a template. Target sequences were aligned to template sequences using MAFFT v7.453 L-INS-i. 50 preliminary models of each complex were constructed and scored using the MODELLER objective function (molpdf), DOPE score and DOPEHR. Each score was scaled to units of standard-deviation across the preliminary models, and the 4 structural models of each complex having the best average of scaled scores were selected. The topscoring models were used as starting points for replicate molecular dynamics simulations. For each structural model, molecular dynamics simulations were executed using GROMACS v2019.2. The amber99sb-ildn force eld and the tip3p water model were used. Initial dynamics topologies were generated using the GROMACS pdb2gmx algorithm with default parameters. Topologies were relaxed into simulated solvent at pH 7 using a 50,000-step steepest-descent energy minimization. The system was then brought to 300K using a 50-ps dynamics simulation under positional restraints, followed by pressure stabilization for an additional 50 ps. Unconstrained molecular dynamics were run for 60 ns using a 0.002-ps integration time step, with the system sampled every 5 ps, following a 10-ns burn in. Simulations were run using Particle-Mesh Ewald electrostatics with cubic interpolation and grid spacing of 0.12 nm. Van der Waals forces were calculated using a force-switch cutoff of 0.8 nm. Nose-Hoover temperature coupling, with protein, and non-protein systems coupled separately and the period of temperature uctuations set to 0.5 ps were also used. Pressure coupling was applied using the Parrinello-Rahman approach, with a uctuation period of 1.0 ps. Non-bonded cutoffs were treated using buffered Verlet lists.
From each dynamics simulation, the central structure was inferred by calculating pairwise root mean square deviations between every pair of simulation samples and identifying the sampled structure most equidistant to the others, using the g cluster function in GROMACS. The root mean square uctuation (RMSF) of each residue was measured over each dynamics simulation. Hydrogen bonds between SOCS1 or SOCS1 KIR and JAK2 were inferred using a radius cutoff of 0.35 nm and an angle cutoff of 30 degrees, and the proportion of simulation samples from which each residue formed a hydrogen bond with JAK2 was calculated. The minimum distance between each residue in SOCS1 or SOCS1 KIR and JAK2 at each sampled time point during the dynamics simulation was calculated, and the proportion of simulation samples from which each residue had at least 1 atom within 0.38 nm from an atom in the JAK2 protein was reported. Signi cance of differences in RMSF, hydrogen bonding and JAK2 contacts were assessed using the 2-tailed, 2-sample independent t-test, assuming unequal variances estimated across 4 replicate molecular dynamics simulations started from different structural models.

Evaluation of topical SOCS1 KIR for Safety in equine eye
To initially assess the safety of the peptide within the equine eye, four experimental, healthy horses (lacking ERU, 2 mare and 2 gelding) were purchased. A priori power analysis established that 4 equine subjects (eight total eyes) would be su cient to assess a signi cant change in ERG measurements, based on historical data from the institution. No exclusion criteria were made in obtaining healthy, experimental horses. Investigator (C.P) was blinded during administration, receiving deidenti ed peptide and placebo control groups. The horses initially received complete ophthalmic and physical examinations and received electroretinography (ERG) in both eyes to establish baseline pro les. Each of the four horses received 200 µg of SOCS1 KIR topically in one eye twice a day for two weeks or intravitreally once in one eye. Carrier control solution was administered in the other eye, serving as control. As such comparisons between eyes, either receiving peptide treatment or not, were made both within each individual horse and between horses to assess safety. ERGs, measuring a-and b-wave potentials and icker responses were performed at days 0, 7 and 14. Complete physical and ophthalmic examinations were also performed at days 0, 7, and 14 to assess SOCS1 KIR mediated changes to ocular structure and function. At 14 days, after ERG and examinations, the experimental horses were euthanized humanely, by intravenous pentobarbital, for histopathological examination of the SOCS1 KIR treated eyes. In addition to isolating and submitting portions of the enucleated eyes to core facilities for independent evaluation, the ocular aqueous and vitreous components were collected and frozen for future use.
Open label ERU Study Enrollment Criteria: A priori ERU patients with con rmed ERU but lacking severe ophthalmic decrements (evidence of chronicity), were optimal for enrollment in clinical trial. However, given the unmet need presented by ERU, horses with uncontrolled ERU-mediated in ammation were also enrolled (even with ophthalmic decrement), given that peptide e cacy could be assessed. Reduction in hyperemia was established as the primary endpoint evaluation of peptide e cacy. A priori power analysis established that nine patients would be required to assess a signi cant decrease in hyperemia, based on historical data from the institution. Ten total patients were enrolled through direct contact with Dr. Plummer. Beyond No exclusions were made, with all participants noted in Table 1. All procedures were conducted on equine patients subsequent to owner consent.

Evaluation of SOCS1-KIR e cacy in ERU Horses
Ten horses (7 gelding and 3 mare) diagnosed with ERU were enrolled in a short-term, open-label trial to assess the e cacy of topical SOCS1 KIR. The horses of varied breed (see Table 1, aged 5-21) enrolled in the trial, presenting with acute or insidious disease, were admitted into the University of Florida Veterinary Hospital for 4-7 days to begin treatments with topical SOCS1 KIR. The horses admitted to the clinic were closely evaluated for e cacy and possible negative effects of the treatment. Examinations included intraocular pressure measurement, slit lamp biomicroscopy, and direct and indirect ophthalmoscopy as possible. 200 µg of SOCS1 KIR was administered in 100 µL topically, which was a small volume that prevented re ex tear formation and possible peptide elimination. Seven of 10 patients presented with bilateral disease for a total evaluation of 17 eyes to assess peptide e cacy (Table 1). After hospitalization, ERU patients were returned to their owners, who continued peptide administration from home. The horses underwent complete physical and ophthalmic examinations at day 0, day 3, day 14, and day 42. During the ophthalmic examinations, the horses were scored for discomfort, hyperemia, and aqueous are using a modi ed MacDonald-Shadduck System 30 by both the attending veterinary ophthalmologist and four additional masked veterinary ophthalmologists. Safety outcomes at each observation period included: (i) ocular irritation scores (utilizing the modi ed MacDonald-Shadduck scoring system-); (ii) number of new cases of ocular infections; (iii) number of horses affected with peptide-mediated damage to the eye; (iv) intraocular pressure (mmHg); and (v) ERG b-wave amplitudes to assess retinal function.

IACUC Statement
All procedures performed on animals were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Florida and were conducted in strict accordance of the approved guidelines.
This study did not adhere to the essential 10 ARRIVE guidelines as it was a pilot study to assess the feasibility of a larger, future study. Speci c rationale is as follows: Given the novelty of the use of topical SOCS1-mimetic peptide, the administration of peptide in this pilot study was ethically conducted in openlabel fashion, without randomization, so that rescue medications could be administered, if necessary. As, such blinding did not occur in the topical administration of the SOCS1-mimetic peptide to all 10 horses enrolled in the trial. A single investigator (C.P.) was aware of the drug allocations and the results of clinical evaluations. However, 4 blinded veterinarians were utilized to obtain the clinical scoring obtained in Figure 4E. Given the open enrollment utilized in this pilot study and the administration of drug by patient owners at home, confounders could not be controlled. Placebo medications were not utilized, although SOCS1 mimetic peptide was provided as compassionate use as speci c owners noted symptom resumption during drug dry out period (not statistically analyzed).

Statistics
Experimental data are presented as mean ± standard error of the mean (SD). All statistical analyses were performed using GraphPad Prism version 8 software (GraphPad Software, La Jolla, CA, USA). For the in vivo assessment of ERU recovery, paired students t tests were utilized. The data were deemed statistically signi cant if P≤0.05. Linear, semi-logarithmic, and one site -speci c binding curves were considered to have a good t if R-squared≥0.95.

Results
SOCS1 is highly conserved within vertebrates, and SOCS1-KIR peptide interacts with equine Jak2.
We have previously shown that the topical administration of a peptide corresponding to the kinase inhibitory region of murine SOCS1 (SOCS1-KIR), DTHFRTFRSHSDYRRI, was safe and prevented induced uveitis in murine and rat models of disease 3,20 . Given that horses and humans develop spontaneous recurrent uveitis, and that equine recurrent uveitis (ERU) is a major cause of sight de cits in horses, we proposed to assess the translatability of our rodent ndings to equine disease. To predict e cacy of our SOCS1-KIR peptide in the treatment of ERU, we utilized bioinformatic tools to compare the similarity between our peptide mimetic and the SOCS1 kinase inhibitory region of several animal species. Ten SOCS1 protein sequences were retrieved from NCBI: 6 from mammals, 1 avian, 1 reptilian, 1 amphibian, and 1 sequence from bony sh. The sequences were used to generate a multiple sequence alignment using the MultAlin software. The multiple sequence alignment was then annotated in Jalview and the regions surrounding KIR were removed ( Figure 1A). This alignment demonstrated high amounts of conservation among all mammalian KIR sequences, with strong conservation among other nonmammalian vertebrates. Between the SOCS1 KIR mimetic peptide, and the KIR of Equus caballus, there were only two changes in amino acids. The rst substitution was a conservative shift from glutamate to aspartate. The second difference was at the 11th amino acid position with a serine present in the mimetic peptide sequence compared to alanine in Equus caballus. This change to serine residue was found in several other species. Additionally, NCBI's BLASTp 31 analysis demonstrated 88% identity and 93% positive residues between the SOCS1-KIR mimetic and the corresponding sequence of SOCS1 from Equus caballus. The trimmed sequences were subsequently used to generate a logo of the consensus sequence ( Figure 1B). The sequence of the SOCS1 KIR mimetic peptide was identical to the consensus sequence except the serine to alanine shift at residue 11. Additionally, the 10 full length SOCS1 sequences were used to generate phylogenetic trees using Phylogeny.fr ( Figure 1C). The phylogenetic trees followed the generally accepted path of vertebral evolution, with closely clustered mammals forming a monophyletic group and Danio rerio (a sh species) being shown as the most distant related species. These results, in combination, demonstrate that the KIR region of SOCS1 is highly conserved among vertebrate species, particularly mammals, suggesting translatability of the SOCS1-KIR mimetic in the treatment of ERU.
Endogenous SOCS1 binds to the activation loop of JAK2, inhibiting both autophosphorylation at tyrosine residue pY1007 and subsequent cellular programming that drives in ammation 32,33 . Given the homology of SOCS1-KIR mimetic to the corresponding region of equine SOCS1, we next assessed the conservation of Jak2 activation loop between putative horse, human, mouse, rat, and bird species. As can be seen in Figure 2A the activation loop of Jak2, postulated to interact with SOCS1, is 100% conserved between the indicated species.
To con rm previous publications demonstrating the binding of the SOCS1-KIR mimetic peptide to the autophosphorylation site of pJak2 (Jak2 1001-1013) 18,29 , direct and competitive in vitro binding assays were conducted. The direct binding assay showed that biotinylated pJak2 (1001-1013), but not control peptide, bound to plate associated SOCS1-KIR mimetic peptide in a dose dependent manner which was denoted by increased absorbance, yielding a dissociation constant (Kd) of 1.7 µM ( Figure 2B). Competitive inhibition binding was next conducted, where a xed concentration of biotinylated pJAK2 (1001-1013) sequence was preincubated with increasing concentrations of SOCS1-KIR mimetic peptide prior to incubation with plate bound SOCS1-KIR peptide. As can be seen in Figure 2C, pre-incubation of pJak2 (1001-1013) with increasing concentrations of soluble SOCS1 KIR yielded a semi-logarithmic decrease in the signal intensity of pJak2 (1001-1013) binding to plate bound SOCS1-KIR peptide (R 2 ≥0.95). These results were consistent with the previous studies showing SOCS1-KIR binding to the peptide pJak2 (1001-1013), which corresponds to the catalytic activation domain of the native peptide 34 , which is 100% conserved among humans, horses, rats, and mice.
We next utilized structural dynamics to evaluate the binding of SOCS1 KIR peptide to equine JAK2. The structural models of the SOCS1 KIR-JAK2 complex were inferred through homology modeling using the empirical structure of human SOCS1 bound to JAK1 35 . Four replicate molecular dynamics simulations of the SOCS1 KIR-JAK2 complex were conducted for 50 ns, with simulations of full-length equine SOCS1 bound to JAK2 used for comparison. SOCS1 KIR peptide was shown to bind to equine JAK2 in a conformation very similar to that of the N-terminal region of full-length horse SOCS1 (Figure 2C and video). In the central complex obtained from molecular dynamics, the unstructured SOCS1 KIR N-terminal tail inserted into a largely hydrophobic cleft formed by the JAK2 β8-α6 loop as well as parts of α6 and α10 helices, with the short SOCS1 KIR α1-helix being stabilized by JAK2 α10 36,37 . This conformation was similar to what was observed in full-length SOCS1-JAK2 simulations and in the empirical human SOCS1-JAK1 complex. No strong structural clashes or repulsive interactions were observed between SOCS1 KIR and horse JAK2 in the native complex conformation. Together these results suggest that SOCS1 KIR likely binds horse JAK2 via a conserved, near-native structural interface.

SOCS1-KIR peptide is safe for the equine eye
To initially assess the safety of the peptide within the equine eye, two experimental, healthy horses (lacking ERU) were initially given complete ophthalmic and physical examinations followed by electroretinography (ERG) in both eyes to establish baseline ocular pro les. ERG is a well-established method of assessing gross physiological changes within an intact retina 20 . The horses then received 200 µg of SOCS1-KIR, or carrier topically in one eye twice a day for two weeks. ERG, measuring a-and b-wave potentials and icker responses, and physical examinations were performed at days 0, 7, and 14 to assess SOCS1-KIR mediated changes to ocular structure and function. At 14 days, after ERG and examinations, the experimental horses were euthanized for histopathological examination of the SOCS1-KIR treated eyes. Signi cantly, physical examinations, ERG, and histological examination showed that SOCS1-KIR treated equine eyes were indistinct from the control eye or baseline readings ( Figure 3). As it was possible that topical SOCS1-KIR did not effectively penetrate the ocular barriers to affect the interior of the eye, the effect of intravitreal injection of SOCS1-KIR was evaluated in two additional horses. One single intravitreal injection of 200mL (0.5 mg/ml) SOCS1-KIR was performed in one eye each of two horses. Again, horse evaluations at 7 and 14 days, followed by independent histopathologic evaluation of enucleated eyes, revealed no distinctions between SOCS1-KIR treated eyes versus control. Together, our results show that SOCS1 KIR administration was safe to the eye in either topical or intravitreal administrations.
Given that topical and intravitreal SOCS1-KIR treatments were safe for experimental horses, we next conducted a pilot open-label trial where we tested our peptide treatment on equine patients possessing ERU. In our pilot trial 10 horses were enrolled, with a total of 17 eyes treated (Table 1). SOCS1-KIR was initially administered as a monotherapy to 5 patients with the remaining 5 receiving SOCS1-KIR in addition either atropine, or a combination of atropine and diclofenac ( Table 1). The horses affected with acute ERU were hospitalized and treated with topical SOCS1-KIR (200 µg in 100 µl) twice a day at the University of Florida Veterinary Hospital for 4-7 days. During hospitalization, no horses experienced untoward treatment effects (i.e., ocular infections, irritation beyond what they experienced as part of their endogenous disease, corneal ulceration, ocular infections or declinations of comfort or sight.). After hospitalization, ERU patients were returned to owners who then continued peptide administration at home. Over a six-week period, most equine patients showed a visible reduction in hyperemia denoted in Figure 4A, which reached a statistically signi cant 40% reduction in clinical scoring over the 6-week evaluation period ( Figure 4C, p<0.01), Additionally, a 50% reduction in aqueous are ( Figure 4D) (p<0.01), and a near complete reduction in overall discomfort (p<0.05) ( Figure 4B) was observed over the same period. Given the open-label design of the clinical trial, we next conducted a blinded veterinary scoring of randomly assorted ocular photographs from ERU patients taken either prior, or subsequent to SOCS mimetic peptide treatment. As can be seen in Figure 4E, blinded scoring yielded a statistically signi cant, 75% reduction in clinical scoring by 6 weeks of treatment. (Figure 4). Notably, one of the seven patients (patient 2) presenting with bilateral disease and minimal sight in one eye, had signs of very modest clinical improvement with SOCS1-KIR (2 mg/ml) administration with in ammation persisting. In this severe ERU patient, rescue medications in combination with SOCS1-KIR were unable to preserve sight, resulting in the euthanasia of the patient. However, resolution of in ammatory processes more strongly coincided with SOCS1-KIR administration in eight of the remaining 9 horses, although 4 horses did receive diclofenac and/or atropine which served to further alleviate pain associated with disease. Additionally, four horses received the topical (NSAID) diclofenac because of either persistent in ammation, or because they presented for evaluation already receiving medication (while still exhibiting clinical signs of in ammation that could be followed). It is signi cant, however, that all horses showed improvement without administration of the systemic NSAID unixin meglumine or topical or systemic corticosteroids.
Due to perceived bene t of topical administration of the SOCS mimetic peptide, four owners requested continued use of the peptide at the conclusion of our initial study because of a noted return of in ammation and pathology during the peptide dry-out period. As such, peptide was made available to the owners as compassionate use. Although the results were not quantitated, as they were beyond the scope of our initial study, all owners receiving drug as compassionate care noted subsequent decreases in discomfort and in ammation when SOCS mimetic treatment was resumed. Moreover, no observed drug related negative events were recorded in the three horses receiving SOCS mimetic, administered twice a day for greater that 8 months (Table 1). Together, these data highlight the therapeutic potential of the SOCS1-KIR mimetic in ameliorating the signs, symptoms, and clinical features of ERU.

Discussion
Equine recurrent uveitis (ERU) is an autoimmune disease where activated T lymphocytes invade the normally immune privileged equine eye and promote the destruction of the uveal tract. Despite the current standard of care treatments, equine recurrent uveitis remains a primary cause of ocular impairment in horses, often resulting in eventual blindness. Despite the e cacy of topical steroids for the treatment of ERU, topical steroids are largely ineffective for the treatment of posterior ERU. Additionally, the prolonged use of steroids, as is often the case in the chronic disease ERU, often presents with additional negative side effects. As such, an unmet need remains for better, safer, and more e cacious therapeutic strategies. For the rst time we present data providing a proof of principle for the safe use of a SOCS1 mimetic for the treatment of ERU and demonstrate a clear correlation between topical SOCS1-KIR administration to the equine eye of ERU patients and reduction of ERU associated symptoms within an open-labeled trial. As such, the data presented provide a strong impetus for detailed mechanistic evaluation of SOCS mimetic peptides as a novel treatment for recurrent uveitis.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. AuthorChecklistLarkinE10only.pdf SOCS1KIRboundtopjak2.mp4 Tablewonames.pdf