small molecules

2026-09-03 | Immunosuppressive and biologic agents in the treatment of uveitis due to systemic disease

Purpose: To determine treatment strategy, visual outcome, adverse effects and therapeutic response to immunomodulation in non-infectious posterior uveitis (PU).Design: Retrospective study on 125 patients over 3 years with minimum follow up of 3 years.Materials and Methods: Retrospective study on 125 patients with Non infective PU over 3 years in a tertiary centre in Chennai, India were analysed. Slit lamp bio-microscopy, best corrected visual acuity, tonometry and indirect ophthalmoscopy, tailored laboratory investigations on blood, aqueous or vitreous samples, and ancillary investigations were done. All patients had active posterior uveitis in at least one eye. Immunosuppressives or/and biologics with or without corticosteroids were administered.Results: Autoimmune PU occurred in 39% males and 61% females. Median age was 47years (21 to 65 years). Immunomodulators were used in 32%, biologics in 18% and combination treatment in 50%. Sixty three percent discontinued medications after a period of 30 to 36 months. Immunosuppressive treatment was continued in 7 patients at maintenance dose for 4 years. Vision improved in 53% and deteriorated in 22% cases. Recurrence occurred in VKH and recalcitrant disease in Behcet’s uveitis. Good response, resolution and visual improvement were noted with serpiginous choroiditis.Conclusion: Immediate corticosteroids combined with immunomodulation over long term reduced inflammation, prolonged remission and preserved vision. Biologics were found to be more commonly associated with adverse effects than immunosuppressives. However serious side effects were observed with methotrexate TB is the commonest complication of treatment in Behcet’s uveitis. Serpiginous choroiditis responds favourably to immunosuppression and tapering steroids with ATT for 9 months is required.

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2026-08-28 | Clinical Features and Visual Outcomes of Pediatric Noninfectious Posterior and Panuveitis.

To describe the demographics, clinical characteristics, treatment patterns, and outcomes of pediatric patients with noninfectious posterior and panuveitis at a single center. Retrospective cohort study of all eyes with posterior and panuveitis between June 2015 and June 2025 that were identified using ICD codes. Charts were reviewed for demographics, clinical characteristics, disease evolution, sequelae, and treatment. Eyes with less than 3 months of follow-up were excluded. Between 2015 and 2025, a total of 12 004 patients (16,810 eyes) were seen for any uveitis diagnosis. Of them, 281 children (449 eyes) were referred for a diagnosis of non-infectious uveitis and 106 eyes of 69 patients met inclusion criteria. Bilateral disease occurred in 50.7% of patients. The leading diagnosis was idiopathic uveitis (51.9% of eyes), with a mean follow-up of 42 months. Nearly all eyes experienced at least one inflammatory flare (mean 1.1 per eye). Topical corticosteroids were most used (60.9% of treated eyes). Ocular sequelae were nearly universal (98.1%), and the proportion of patients with vision 20/200 or worse remained stable from baseline to follow-up (39.1% vs 40.6%). Linear mixed-effects modeling identified glaucoma (β×t =  +0.0141 logMAR/month, p < 0.001) and vitreous opacities (β×t =  +0.0096, p = 0.005) as the sequelae most strongly associated with visual decline. Methotrexate was independently associated with a more favorable visual acuity trajectory (β×t =  -0.0071 logMAR/month, p < 0.001). Pediatric noninfectious posterior and panuveitis is characterized by chronic, bilateral disease with near-universal sequelae. Glaucoma and vitreous opacities were the strongest drivers of visual decline, while methotrexate was associated with visual preservation, supporting its early use in this population.

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2026-07-17 | Demographic and socioeconomic associations with outcomes in pediatric uveitis: An IRIS® registry study

Objective To evaluate the associations of demographic and socioeconomic factors—including race and ethnicity, sex, insurance type, age, and geographic region—with visual outcomes, ocular complications, and the need for ocular surgery in children with non-infectious uveitis Design Retrospective cohort study using the American Academy of Ophthalmology IRIS® (Intelligent Research in Sight) Registry, a national ophthalmic disease registry Participants Pediatric patients with non-infectious uveitis Methods Patients with non-infectious uveitis diagnosed and treated at age ≤18 with ≥1 year follow-up with complete demographic information identified in the IRIS® Registry between January 1, 2013 and December 31, 2019. Insurance type was used as a proxy for socioeconomic status, and analyses accounting for the inclusion of both eyes of the same patient were performed using generalized estimating equations. Multivariable logistic or linear regression were performed to assess whether age, sex, race, region and insurance type were associated with higher risk of poor visual acuity outcomes, complications of uveitis and requirement for ocular surgery. Results Data from 3611 unique patients (5,723 eyes) were included. Compared to White children, Black children were more likely to have a final visual acuity of 20/200 or worse and develop glaucoma and cystoid macular edema (OR for White vs Black children for 20/200 or worse vision 0.59, 95% CI 0.42–0.82; P<0.05). Compared to children with private insurance, those with Medicaid were more likely to have a final visual acuity of 20/200 or worse, as well as suffer from amblyopia, posterior synechiae, and band keratopathy (OR for private vs Medicaid for 20/200 or worse vision 0.50, 95% CI 0.37–0.67; P<0.05 for all). Children with age ≤12 years were more likely to develop band keratopathy and amblyopia compared to those 13-18 years old (amblyopia OR 4.99, 95% CI 3.00–8.31; band keratopathy OR 2.62, 95% CI 1.89–3.63; P<0.001 for both). Conclusion Socioeconomic and demographic factors associated with poorer clinical outcomes in pediatric non-infectious uveitis include younger age at presentation, Black

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2026-06-25 | Uveitis in spondyloarthritis: clinical patterns and differences between axial and peripheral forms.

The association between uveitis and spondyloarthritis is well established. However, its characterization across the different types of spondyloarthritis remains limited in the literature. Therefore, this study aimed to perform a comparative characterization of uveitis in the various types of spondyloarthritis. Retrospective observational study that included patients with non-infectious uveitis and spondyloarthritis from a multidisciplinary uveitis clinic. A descriptive analysis was performed across the different subtypes of spondyloarthritis, followed by a comparative analysis regrouping patients into axial and peripheral SpA categories. 163 patients with spondyloarthritis-associated uveitis were included, comprising radiographic axial spondyloarthritis (49%), non-radiographic axial spondyloarthritis (21%), spondyloarthritis associated with inflammatory bowel disease (13%), psoriatic arthritis (12%), and peripheral spondyloarthritis (4%). Anterior uveitis (97%), acute relapsing course (79%), and alternating laterality (47.4%) were predominant in the overall sample. When comparing axial versus peripheral forms, significant differences were observed: intermediate, posterior, and panuveitis locations occurred exclusively in the peripheral forms, which also showed higher frequencies of chronic courses (p < 0.001), bilateralism (p < 0.05), and greater use of systemic therapy (p = 0.05). Regarding this treatment to control uveitis, 28.2% of patients required immunomodulatory therapy (more sulfasalazine in axial forms, and methotrexate in peripheral) and 17.8% required biologic therapy. Biologic discontinuation was higher in peripheral forms (p = 0.059). Variables predicting greater need for systemic therapy included chronic course, bilateralism, higher number of annual episodes, younger age of onset, peripheral joint involvement, and presence of vitritis (all p < 0.05). Acute anterior uveitis constitutes the most frequent pattern in all spondyloarthritis types. However, peripheral forms exhibit a higher prevalence of non-anterior, chronic, and bilateral uveitis, and, additionally, appeared to require greater use of immunomodulatory therapy. Key Points • Understanding and distinguishing the ocular inflammatory processes associated with SpA may have important therapeutic and prognostic implications. • Although acute recurrent anterior uveitis was the most frequent patternacross all SpA subtypes, in the peripheral SpA group (pSpA, IBD-SpA, and PsA) a higher prevalence of intermediate, posterior, panuveitis, chronic course, and bilateral uveitis was observed. • The peripheral SpA group (pSpA, IBD-SpA, and PsA) appeared to require greater use of immunomodulatory drugs (csDMARDs or biologics) for control of the ocular condition, suggesting the need for closer monitoring and tailored therapeutic strategies.

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2026-06-19 | Bromfenac 0.09% as adjunct to anti-VEGF for the treatment of macular edema secondary to noninfectious uveitis

<p><strong>Background: </strong>Uveitis is a major cause of visual impairment and blindness and macular edema is the major risk factor. Uveitic macular edema (UME) mechanism is primarily through blood-retinal barrier breakdown driven by inflammatory mediators such as prostaglandins and vascular endothelial growth factor (VEGF). Corticosteroids are the main treatment but can cause significant side effects leading to the use of alternatives including topical non-steroidal anti-inflammatory drugs (NSAIDs) and intravitreal anti-VEGF agents. Bromfenac is an FDA-approved NSAID for postoperative inflammation but its efficacy in UME is not clear. We report a case of UME secondary to non-infectious uveitis managed with topical bromfenac in combination with intravitreal aflibercept.</p> <p><strong>Case Presentation: </strong>A 13-year-old female with a history of chronic intermittent bilateral posterior uveitis presented for follow-up 6 months after stopping biologic treatment and 2 years of stable disease activity. Uncorrected visual acuity was 6/12 in both eyes (OU) and recurrent macular edema was found in the right eye (OD) with central foveal thickness (CFT) of 718 &micro;m. The patient was started on bromfenac 0.09% twice daily and received a single intravitreal anti-VEGF injection. At one-week follow-up, the CFT decreased to 419 &micro;m. At four-week follow-up, the CFT decreased to 318 &micro;m OD and there was significant improvement of the macular edema.</p> <p><strong>Conclusion: </strong>Bromfenac 0.09% as adjunctive to anti-VEGF injection may be an effective treatment for macular edema secondary to non-infectious uveitis.</p>

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antibodies

2026-09-26 | Biological and Targeted Therapy in Non-Infectious Uveitis: Current Evidence and Future Perspectives.

Non-infectious uveitis (NIU) comprises a group of immune-mediated inflammatory diseases of the uvea that frequently affect people of working age. If inflammation is not controlled promptly, it may lead to permanent structural damage and visual loss. Prolonged corticosteroid use increases the risk of adverse effects. Contemporary treatment aims not only to control inflammation, but also to minimise dependence on corticosteroids. This narrative review examines the efficacy, safety, and place of biological and targeted therapies in the treatment of NIU. Adalimumab is the best-studied biological agent for intermediate, posterior, and panuveitis, as well as for uveitis associated with juvenile idiopathic arthritis. Infliximab has an important role in severe Behçet-associated uveitis and occlusive retinal vasculitis. Among the biological therapies with mechanisms of action other than TNF-α inhibition, tocilizumab is the best studied, particularly in refractory uveitic macular oedema. Janus kinase inhibitors (JAK inhibitors) are a rapidly developing class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs). Clinical studies in NIU have shown variable efficacy and indicate their potential as a future therapeutic option. Treatment selection should be individualised and should take into account the anatomical form and severity of uveitis, the presence of systemic disease, macular oedema or occlusive retinal vasculitis, age and comorbidities, and the response to previous therapy. Therapeutic drug monitoring, biomarkers, and quantitative imaging parameters represent promising approaches to treatment personalisation; however, their clinical utility requires validation in prospective studies, and they are not currently part of routine clinical practice in non-infectious uveitis.

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2026-09-17 | Real-World Safety and Effectiveness of Adalimumab in Patients with Non-Infectious Intermediate, Posterior, or Panuveitis: A Post-Marketing Surveillance Study in Korea.

This post-marketing surveillance study reports the real-world safety and effectiveness of adalimumab (Humira®, AbbVie Inc.) among patients with non-infectious intermediate, posterior, or panuveitis (NIIPPU) in Korea. The study was conducted at 17 medical centres from January 2018 to July 2020. Safety (155 patients) was analysed by collecting adverse events (AEs) and adverse drug reactions (ADRs) data. Effectiveness assessments (148 patients) included anterior chamber cell grade, vitreous haze grade, and best corrected visual acuity (BCVA) change. At baseline, the mean duration of uveitis was 3.9 ± 4.0 years (n = 101) and the mean number of relapses in the past year was 2.5 (n = 52). The most common anatomical uveitis phenotype was panuveitis (n = 110, 71.0%). One patient received prior infliximab; within the previous 3 months, 75.4% and 93.3% of patients received glucocorticoids and immunosuppressants, respectively. The mean daily corticosteroid dose decreased from 9.7 ± 7.8 mg at the start of the study to 6.6 ± 6.0 mg at the end of the study (p < 0.0001). AEs and ADRs were reported in 13 patients (8.4%, 1.9% serious) and 5 patients (3.2%), respectively. The most common ADR was injection-site discomfort. Twenty-nine patients (18.7%) discontinued adalimumab within 6 months; 34 patients discontinued during follow-up, most commonly for cost issues (64.7%). Three patients discontinued adalimumab due to AEs. Regarding effectiveness, from baseline to 22 weeks, anterior chamber inflammation and vitreous haze tended to improve significantly; there was no BCVA worsening. In the real-world setting, adalimumab treatment showed an acceptable safety profile, with serious AEs reported in three patients but no serious ADRs related to adalimumab, and demonstrated potential effectiveness in Korean patients with NIIPPU.

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2026-08-08 | Adalimumab Therapy Reduces Treatment Burden in Multifocal Choroiditis/Punctate Inner Choroidopathy.

This study aims to demonstrate the efficacy of adalimumab (ADA) in reducing overall treatment burden in a cohort of patients with idiopathic multifocal choroiditis (MFC)/punctate inner choroidopathy (PIC). This is a retrospective case series of eyes classified as having idiopathic MFC/PIC using standard multi-modal imaging, including color fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. LogMAR best-corrected visual acuity (BCVA), doses of prednisone and other immunomodulatory therapies (IMT), injections of corticosteroids or anti-vascular endothelial growth factor (anti-VEGF), and breakthrough flares were collected at baseline (initiation of ADA), 12 months from baseline, and last follow-up. Twenty-five patients (21 females, 41 eyes) were included. Mean follow-up time was 51.4 ± 35.2 months (range 9.2-126.6). Mean LogMAR BCVA was 0.35 ± 0.48 at baseline and 0.34 ± 0.55 at last follow-up (p > 0.5). Mean prednisone dosage decreased significantly from 15.76 ± 18.69 mg/day at baseline to 0.23 ± 1.1 mg/day at the last follow-up (p < 0.0001). Thirty eyes received steroid or anti-VEGF injections at baseline; this decreased to one at the last follow-up (p < 0.0001). Similarly, eight patients received other IMT at baseline, but only one continued to receive supplemental IMT at the last follow-up (p < 0.05) at a decreased dosage. Six patients experienced disease flare-up within the first 12 months of treatment, and three patients flared between 12 months and last follow-up. Adalimumab therapy demonstrated a significant steroid-sparing effect in addition to vision preservation and reduction in both anti-VEGF injections and IMT.

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2025-10-21 | Adalimumab in non-infectious uveitis, towards a real-world therapeutic paradigm beyond inflammation control: A multicenter cross-sectional study.

To evaluate the real-world long-term efficacy and safety of adalimumab (ADA) in refractory non-infectious uveitis (NIU), analyzing clinical outcomes, treatment adjustments, and the potential role of ADA trough levels (ADA TL) in therapeutic response. By identifying factors influencing response, our study aims to contribute to a more personalized approach. A multicenter, cross-sectional, observational study was conducted in NIU patients receiving ADA for ≥ 6 months. Disease activity was defined using the Standardization of Uveitis Nomenclature (SUN) criteria, and patients were categorized as responders (R) or non-responders (NR). The study assessed corticosteroid (CS) and immunosuppressive therapy adjustments, relapse rates, adverse events (AEs), patient-reported outcomes (PROMs), and the relationship between serum ADA TL, anti-drug antibodies (AAA), and clinical response. A total of 52 patients (91 eyes) with a median disease duration of 6.5 years (IQR 3.0–11.5) were included. Anterior uveitis was the most frequent subtype (34.6%), followed by panuveitis (26.9%), posterior (25%) and intermediate uveitis (13.5%). ADA therapy resulted in a significant reduction in systemic CS and c-DMADs. At the study visit, 65.4% of patients achieved complete inflammatory quiescence, with anterior (OR = 0.06, P = 0.009) and posterior uveitis (OR = 0.11, P = 0.04), being associated with a higher likelihood of response. ADA TL and AAA did not correlate with clinical response (median [IQR]: R = 8.5 [3.9–14.8] µg/mL vs. NR = 10.3 [7.9–14.5] µg/mL). AEs were reported by 32.7% of patients, predominantly mild-to-moderate infections, fatigue, and headaches. No significant differences in efficacy, safety, or relapse rates were observed between original ADA and biosimilars. Original ADA and biosimilars demonstrate long-term effectiveness and safety in NIU, reducing the need for systemic therapy, with comparable effectiveness and safety. PROMs further revealed that improvements in vision-related QoL were primarily driven by general vision perception, underscoring the subjective impact of treatment beyond objective inflammation control. While serum ADA levels were influenced by some clinical variables, they did not correlate with response to treatment.

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2025-10-03 | Evaluating the Effectiveness of Escalating to Weekly Adalimumab Dosing for the Treatment of Non-infectious Uveitis: A Multi-Center Study.

To evaluate the effectiveness of adalimumab (ADA) dose escalation in patients with non-infectious uveitis who are inadequately controlled with standard dosing. Multi-center retrospective interventional case series. Patients with non-infectious uveitis active on standard biweekly ADA dosing who had treatment escalated to weekly ADA dosing at 6 tertiary referral centers. Demographic data and clinical findings were assessed at the time of ADA dose escalation and 6-months later. Mixed model analysis was performed to analyze clinical outcomes and to assess predictive factors of success. Treatment success composite criteria included: (1) disease quiescence (≤0.5+ anterior chamber cell, ≤0.5+ vitreous haze, inactive retinal/choroidal lesions); (2) prednisone ≤7.5 mg/day; and (3) ≤2 drops/day of prednisolone or equivalent (4) no treatment discontinuation. Fifty patients (44.4±21.2 years old, n=35 female) from 6 tertiary referral centers were included. At 6 months following ADA escalation (median 184 days), 52% of patients had achieved treatment success. Specific inflammatory signs significantly reduced after ADA escalation included anterior chamber cell grade (p=0.025) and presence of active retinal/choroidal lesions (p=0.010). Prednisone was decreased from >7.5 mg daily to lower doses in 63% (p=0.015). The odds ratio for treatment success was 6.88 for patients with posterior uveitis (p=0.024) and 0.14 (p=0.005) for patients with panuveitis. The hazard ratio for treatment success was 3.73 (p=0.009) for eyes with active retinal vasculitis at the time of ADA escalation. Escalation from standard biweekly ADA dosing to weekly ADA dosing achieved treatment success in over half of the patients. Posterior uveitis predicts a favorable chance of success, whereas panuveitis conveys a lower success rate.

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gene therapies

2024-04-15 | AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Abstract Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

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2022-03-23 | Therapeutic Applications of Adeno-Associated Virus (AAV) Gene Transfer of HLA-G in the Eye

The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that demonstrate efficacy in animal models of disease, including intracorneal delivery of AAV-HLA-G to treat corneal inflammation and prevent corneal graft rejection, subconjunctival injection of AAV-HLA-G for ocular graft vs. host disease and potentially dry eye disease, and intravitreal injection of AAV-HLA-G to inhibit uveitis. Furthermore, due to the anti-vascular function of HLA-G, AAV-HLA-G may be an effective therapy for posterior ocular diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization. Therefore, AAV-mediated gene transfer of HLA-G may be an effective treatment for common immune-mediated, inflammatory, and neovascular diseases of the eye.

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2021-06-18 | Recent advances in the management of non-infectious posterior uveitis.

To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU). We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials. The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects. Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic agents.

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2019-12-27 | AAV-mediated expression of HLA-G1/5 reduces severity of experimental autoimmune uveitis

Non-infectious uveitis (NIU) is an intractable, recurrent, and painful disease that is a common cause of vision loss. Available treatments of NIU, such as the use of topical corticosteroids, are non-specific and have serious side effects which limits them to short-term use; however, NIU requires long-term treatment to prevent vision loss. Therefore, a single dose therapeutic that mediates long-term immunosuppression with minimal side effects is desirable. In order to develop an effective long-term therapy for NIU, an adeno-associated virus (AAV) gene therapy approach was used to exploit a natural immune tolerance mechanism induced by the human leukocyte antigen G (HLA-G). To mimic the prevention of NIU, naïve Lewis rats received a single intravitreal injection of AAV particles harboring codon-optimized cDNAs encoding HLA-G1 and HLA-G5 isoforms one week prior to the induction of experimental autoimmune uveitis (EAU). AAV-mediated expression of the HLA-G-1 and -5 transgenes in the targeted ocular tissues following a single intravitreal injection of AAV-HLA-G1/5 significantly decreased clinical and histopathological inflammation scores compared to untreated EAU eyes (p < 0.04). Thus, localized ocular gene delivery of AAV-HLA-G1/5 may reduce the off-target risks and establish a long-term immunosuppressive effect that would serve as an effective and novel therapeutic strategy for NIU, with the potential for applications to additional ocular immune-mediated diseases.

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2018-08-01 | Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: Preclinical evaluation of the medicinal product

Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-α receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-α, for non-viral gene transfer into the ocular ciliary muscle. Electrotransfer of pEYS606 in the ciliary muscle significantly reduced ocular inflammation in two well-established rat models of uveitis, the endotoxin-induced uveitis (EIU) and the experimental autoimmune uveitis (EAU). In addition, in EAU, a significant protection of photoreceptors was demonstrated after pEYS606 treatment. The improved pharmacokinetic profile of intraocularly-secreted protein as compared to direct intravitreous injection of recombinant protein allowed to demonstrate Protein 6 efficacy at very low concentrations. Based on these results, a phase I/II clinical trial is conducted [ClinicalTrials.gov Identifier: NCT03308045].

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oligonucleotides

2023-10-27 | Expression of Long Non-Coding RNAs in Activated Human Retinal Vascular Endothelial Cells.

Retinal endothelial cell activation is a central event in non-infectious posterior uveitis. There is recent interest in long non-coding (lnc)RNA-targeted therapeutics for retinal diseases. We aimed to identify human retinal endothelial cell lncRNAs that might be involved in activation. Eleven candidate lncRNAs were identified: GAS5, KCNQ1OT1, LINC00294, MALAT1, MEG3, MIR155HG, NEAT1, NORAD, OIP5-AS1, SENCR, TUG1. Expression was assessed by RT-PCR in human retinal endothelial cells, at baseline and following activation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α. IL-1β significantly upregulated MEG3 and SENCR at 4 and 24 hours; LINC00294, NORAD, OIP5-AS1 and TUG1 at 24 hours; and MIR155HG at 4, 24 and 48 hours; but downregulated GAS5 at 24 and 48 hours. TNF-α significantly upregulated KCNQ1OT1, LINC00294, MEG3, NORAD and SENCR at 4 hours; SENCR and TUG1 at 24 hours; and MIR155HG at all time points. Future studies involving manipulation of MIR155HG may be warranted to explore potential therapeutic applications for non-infectious posterior uveitis.

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2023-02-07 | Selective Transcription Factor Blockade Reduces Human Retinal Endothelial Cell Expression of Intercellular Adhesion Molecule-1 and Leukocyte Binding

The interaction between leukocytes and cytokine-activated retinal endothelium is an initiating step in non-infectious uveitis involving the posterior eye, mediated by cell adhesion molecules. However, because cell adhesion molecules are required for immune surveillance, therapeutic interventions would ideally be employed indirectly. Using 28 primary human retinal endothelial cell isolates, this study sought to identify transcription factor targets for reducing levels of the key retinal endothelial cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, and limiting leukocyte binding to the retinal endothelium. Five candidate transcription factors-C2CD4B, EGR3, FOSB, IRF1, and JUNB-were identified by differential expression analysis of a transcriptome generated from IL-1β- or TNF-α-stimulated human retinal endothelial cells, interpreted in the context of the published literature. Further filtering involved molecular studies: of the five candidates, C2CD4B and IRF1 consistently demonstrated extended induction in IL-1β- or TNF-α-activated retinal endothelial cells and demonstrated a significant decrease in both ICAM-1 transcript and ICAM-1 membrane-bound protein expression by cytokine-activated retinal endothelial cells following treatment with small interfering RNA. RNA interference of C2CD4B or IRF1 significantly reduced leukocyte binding in a majority of human retinal endothelial cell isolates stimulated by IL-1β or TNF-α. Our observations suggest that the transcription factors C2CD4B and IRF1 may be potential drug targets for limiting leukocyte-retinal endothelial cell interactions in non-infectious uveitis involving the posterior eye.

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2013-05-15 | STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis.

Purpose.: MicroRNA-155 (miR-155) and STAT3 are implicated in uveitis and pathogenic mechanisms of CNS autoimmune diseases. In our study, we used miR-155−/− mice and mice with targeted STAT3 deletion in T cells (CD4-STAT3KO) to investigate roles of miR-155 and STAT3 in the development of experimental autoimmune uveitis (EAU), a mouse model of human uveitis. Methods.: We induced EAU in WT, miR-155−/− , or CD4-STAT3KO mice by immunization with interphotoreceptor retinoid-binding protein/complete Freund's adjuvant (IRBP/CFA) or adoptive transfer of T cells. EAU was assessed by funduscopy and histology. RNA expression was analyzed by quantitative PCR (qPCR), while cytokine production was assessed by fluorescence-activated cell sorting (FACS). Results.: We used a combination of genomic and genetic tools to provide the first evidence that STAT3 binds directly to the miR-155 locus and that STAT3 is required for miR-155 expression. Furthermore, STAT3-dependent increase in miR-155 expression in vivo correlated temporally with onset of EAU, and miR-155−/− or CD4-STAT3KO mice did not suffer EAU. CD4+ lymph node cells from IRBP-immunized WT mice transferred EAU to naïve wild-type (WT) and miR-155−/− mice, while miR-155−/− IRBP-specific T cells did not. Conclusions.: Although miR-155 and STAT3 have been implicated in the etiology of multiple sclerosis (MS), uveitis, or rheumatoid arthritis, their exact roles in these diseases are unclear. We show here for the first time to our knowledge that STAT3 regulates miR-155 expression in Th17 cells. We show further that STAT3 and miR-155 form an axis that promotes the expansion of pathogenic Th17 cells that mediate uveitis. Thus, STAT3 and miR-155 may be therapeutic targets for treating uveitis and other Th17-mediated inflammatory disorders.

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2010-09-01 | Mechanisms of TNFα regulation in uveitis: Focus on RNA-binding proteins

Tumour necrosis factor-α (TNFα) is a key mediator of inflammation and plays a crucial role during the early phase of a host's defence against bacterial, viral and parasitic infections. Persistent production of TNFα occurs in many autoimmune inflammatory diseases, including uveitis, and this is associated with significant tissue damage. Although uveitis represents a phenotypically heterogeneous group of intraocular inflammatory conditions, they have in common raised levels of TNFα in both serum and aqueous humour. Supporting a critical role for TNF activity during uveitis are reports that serum levels of TNFα correlate with disease status as well as the increasing evidence of therapeutic success of anti-TNF agents. TNFα is an archetypal pleiotropic cytokine and when acting systemically acute release may cause profound physiological decompensation. Yet, conversely, at tissue sites TNFα plays important roles governing homeostasis and during chronic inflammation regulating immune responses through control of, for example, macrophage-T cell functions. In a murine model of CD4(+) T cell mediated non-infectious uveitis, experimental autoimmune uveitis (EAU), activation of infiltrating macrophages mediates tissue damage. In EAU, whilst both T cells and macrophages generate TNFα, tissue damaging macrophage activation is dependent upon TNF receptor 1 (p55). TNFα protein production is controlled at the level of transcription, pre-mRNA processing, mRNA stability, translation and retention at the plasma membrane. The p38 MAP kinase and MAPKAP-2 pathway are involved in the post-transcriptional regulation of TNFα and are targeted by a functionally divergent group of cytokines including IL-10 and TGFβ1. Common to many cytokines, TNFα mRNA 3' untranslated region (UTR) contains an AU-rich element (ARE), which drives repression by mRNA-binding proteins (RBPs). These include tristetraprolin (TTP), T cell antigen-1 (TIA-1), TIA-1-related protein (TIAR), human antigen R (HuR) and fragile-X-related protein 1 (FXR1). Disruption of several RBPs can dysregulate TNFα protein production and has, in some cases, been shown to exacerbate chronic inflammatory disease both in mice and in humans. Given that TNFα is central to clearance of infections, yet during chronic inflammation results in tissue damage, understanding the role that RBPs play in the control of TNFα may give rise to opportunities to not only develop targeted therapy for autoimmunity but also redress homeostasis without compromise and risking infection. The study of mRNA stability remains essential for the understanding of intracellular regulatory pathways and molecular mechanisms of pathology for infection, inflammation and degeneration.

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2023-06-02 | IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis

IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.

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2020-07-21 | Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling

Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization.

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