RARE DISEASE
Non-infectious anterior uveitis
Non-infectious anterior uveitis
Non-infectious anterior uveitis
Synonyms: Non-infectious iridocyclitis
Synonyms: Non-infectious iridocyclitis
Synonyms: Non-infectious iridocyclitis
Drug discovery
10
drugs
With orphan designations
Overview
Non-infectious anterior uveitis (NIAU) involves inflammation of the iris and ciliary body, accounting for 80% of non-infectious uveitis cases [9][14]. It is strongly associated with HLA-B27 positivity (20-50% of cases) and systemic autoimmune conditions like ankylosing spondylitis [16][19]. Clinical features include acute-onset ocular pain, photophobia, and anterior chamber cells; untreated cases risk synechiae, glaucoma, and cataracts [3][20].
Burden
Economic: Annual medical costs average $7,834 per patient, rising to $23,619 in blindness-related complications [4][9]
Clinical: 22% risk of chronic/recurrent inflammation, with 15-30% developing secondary glaucoma or cataracts [14][16]
Workforce: Responsible for 5-20% of preventable blindness in developed nations, disproportionately affecting employed adults [9][19][16]
Therapies
First-line: Topical corticosteroids (e.g., prednisolone acetate) with cycloplegics (e.g., cyclopentolate) [3][20]
Refractory/Chronic: Systemic immunomodulators (methotrexate, mycophenolate) or anti-TNF agents (adalimumab) [6][8]
Complication management: Intraocular pressure control with glaucoma medications (30-60% require treatment) [1][4]
Categories: rare ophthalmic disorders
Research Papers
440 drug discovery papers about Non-infectious anterior uveitis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
440 drug discovery papers about Non-infectious anterior uveitis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2024-10-25 | Efficacy and tolerability of subcutaneous repository corticotropin injection in refractory ocular inflammatory diseases.
Repository corticotropin injection (RCI) has been suggested to exert immunomodulatory and anti-inflammatory effects in ocular inflammation. The index retrospective study aimed to evaluate the efficacy and tolerability of subcutaneous RCI in patients with active scleritis or uveitis. Medical records of patients who were diagnosed with different types of active scleritis or uveitis and received RCI for more than six months at a tertiary eye center were reviewed. Patient characteristics including age, sex, comorbidities, clinical findings, treatment details, and adverse events were recorded. A total of 17 eyes of 17 patients were included. Median age was 43 years old and 53% of patients were male. Mean treatment duration was 25.4 ± 15.5 months. Indications for RCI therapy were scleritis (7 anterior and 1 posterior) (47.8%), panuveitis (17.4%), retinal vasculitis (17.4%), chronic/recurrent anterior uveitis (13%), and posterior uveitis (4.35%). RCI was initiated at a dose of 40 to 80 units 3 times weekly. Given the adequate control of inflammation, RCI was successfully discontinued in four patients (23.5%). Prior to RCI therapy, 14 (82.3%) patients were on oral prednisone at an average of 10 mg daily (range 2.5-40 mg), and two (11.7%) patients discontinued prednisone immediately before initiating RCI due to side effects. After six months of therapy, the prednisone dose was reduced in four (23.5%) patients to an average of 3 mg daily (range 1-5 mg) and was stopped in eight (53%) patients. Concomitant immunomodulatory therapies (IMTs) included mycophenolate mofetil (23.5%) and methotrexate (23.5%), and adalimumab (23.5%). Ten patients were on IMTs prior to using RCI, and during the course of treatment, IMT was stopped in two patients and reduced in one. Side effects included insomnia (23%), hypertension (11.7%), lower extremity edema (11.7%), hyperglycemia (11.7%), weight gain (11.7%), and infection (5.8%). RCI may be considered as a potential therapy with acceptable tolerability for patients with non-infectious scleritis or uveitis.
2023-09-01 | Targeted delivery of autoantigen to dendritic cells prevents development of spontaneous uveitis
Restoration of immunological tolerance to self antigens has been a major drive in understanding the mechanisms of, and developing new treatments for, autoimmune and autoinflammatory disease. Sessile dendritic cells (DC) are considered the main instruments underpinning immunological tolerance particularly the CD205+ (DEC205+) cDC1 subset in contrast to DCIR2+ cDC2 which mediate immunogenicity. Targeting DC using autoantigen peptide-antibody fusion proteins has been a well explored methodology for inducing tolerance. Here we show that subcutaneous (s.c.) inoculation of hen-egg lysozyme (HEL)-DEC205 Ig fusion prevents the development of spontaneous uveoretinitis (experimental autoimmune uveoretinitis, EAU) in a transgenic mouse model generated by crossing interphotoreceptor retinol binding protein (IRBP)-HEL (sTg HEL) with HEL specific TCR (sTg TCR) mice. Prolonged suppression of EAU required injections of HEL-DEC205 Ig once weekly, reflecting the half life of s.c. DC. Interestingly, HEL-DCIR2 Ig also had a suppressive effect on development of EAU but less so than DEC205 Ig while it had minimal effect on preventing the retinal atrophy associated with EAU. In addition, HEL-DEC205 Ig was only effective when administered s.c. rather than systemically and had no effect on EAU induced by adoptive transfer of HEL-activated T cells. These data demonstrate the importance of systemic (lymph node) rather than local (eye) antigen presentation in the development of EAU as well as suggest a potential therapeutic approach to controlling sight-threatening immune-mediated uveitis provided relevant antigen(s) can be identified.
2023-07-10 | The multifunctional human ocular melanocortin system.
Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.
2020-09-25 | Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema
Purpose: To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME). Methods: Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) >300 μm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1, IL-6, IL-8, IL-17, MCP-1, TNF-, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3+CD4+FoxP3+ in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels. Results: Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67; CI 95% (0.45-1.00); p = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, C I95%, 1.12-2.56, p = 0.049). Conclusions: Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.
2019-12-23 | A Cell Penetrating Peptide from Type I Interferon Protects the Retina in a Mouse Model of Autoimmune Uveitis
Abstract Experimental autoimmune uveitis (EAU) in rodents recapitulates many features of the disease in humans and has served as a useful tool for the development of therapeutics. A peptide from C-terminus of interferon α1, conjugated to palmitoyl-lysine for cell penetration, denoted as IFNα–C, was tested for its anti-inflammatory properties in ARPE-19 cells, followed by testing in a mouse model of EAU. Treatment with IFNα–C and evaluation by RT-qPCR showed the induction of anti-inflammatory cytokines and chemokine. Inflammatory markers induced by treatment with TNFα were suppressed when IFNα–C was simultaneously present. TNF-α mediated induction of NF-kB and signaling by IL-17A were attenuated by IFNα–C. Differentiated ARPE-19 cells were treated with TNFα in the presence or absence IFNα–C and analyzed by immmunhistochemistry. IFNα–C protected against the disruption integrity of tight junction proteins. Similarly, loss of transepithelial resistance caused by TNFα was prevented by IFNα–C. B10.RIII mice were immunized with a peptide from interphotoreceptor binding protein (IRBP) and treated by gavage with IFNα–C. Development of uveitis was monitored by histology, fundoscopy, SD-OCT, and ERG. Treatment with IFNα–C prevented uveitis in mice immunized with the IRBP peptide. Splenocytes isolated from mice with ongoing EAU exhibited antigenspecific T cell proliferation that was inhibited in the presence of IFNα–C. IFNα–C peptide exhibits anti-inflammatory properties and protects mice against damage to retinal structure and function suggesting that it has therapeutic potential for the treatment of autoimmune uveitis.
small molecules
2026-05-23 | Epidemiology and outcomes of non-infectious paediatric uveitis in the French Caribbean: a 15-year cohort study from a high-income health system in Martinique.
Non-infectious uveitis (NIU) are rare in children but might be associated with substantial visual impairment. Most NIU paediatric cohorts originate from Europe, North America, or Asia, with minimal representation of Caribbean populations. Our study aimed to describe the epidemiology, clinical features, aetiologies and outcomes of paediatric NIU in Martinique. We conducted a monocentre, retrospective cohort study that included all children under the age of 18 diagnosed with NIU at the University Hospital of Martinique between 2010 and 2024. We identified cases through paediatric and ophthalmology registries, medical records, and national hospital databases. We excluded infectious uveitis and non-residents. Incidence estimates used population data. A total of 17 children with NIU were included in the study. 41% were male, with a mean age at diagnosis of 8.7 years (range: 2.5-16) and a median follow-up period of 7.6 years (range: 2.2-11.6). Eleven patients had anterior uveitis (64.7%), and 35.3% had panuveitis. Uveitis was unilateral in 64.7% of patients. The estimated incidence was 1.4 per 100,000 person-years (95% CI 0.83-2.27). The leading aetiology was juvenile idiopathic arthritis, accounting for 58.8% of cases. Systemic biologics were used in 17.6% of patients. Only one child experienced visual loss and required ocular surgery at the final follow-up. The first Caribbean paediatric NIU cohort shows a similar etiological spectrum and good visual outcomes as reported in high-income countries.
2026-04-29 | Demographic and clinical pattern of non-infectious uveitis in the Tripoli Children's Hospital
Uveitis is relatively rare in the pediatric population, but it leads to considerable ocular morbidity. This study aims to describe the clinical, etiological, and treatment features of noninfectious uveitis in Libyan children in a pediatric rheumatology clinic. A retrospective analysis of medical records of pediatric patients who were diagnosed with noninfectious uveitis from January 2000 to December 2021 at the pediatric rheumatology clinic at Tripoli Children's Hospital, Tripoli, Libya, was conducted. All the cases of uveitis in patients under 18 years of age at diagnosis were included. The collected data included age at diagnosis, anatomical location of uveitis, laterality, associated systemic disease, used medications, and visual outcome. 75 patients (137 eyes) comprised the study sample. The mean age at the onset of uveitis was 8.9 ± 3.5 years. The female-to-male ratio was 1: 1.7. Pan uveitis was the most frequent anatomical location (54.7%), followed by anterior uveitis (36.0%), posterior (8.0%), and intermediate (1.3%). The bilateral eye was involved in 82.7%, and the unilateral eye was involved in 17.3%. The common causes of non-infectious uveitis are chronic idiopathic (52.0%), which was the most frequent etiology. Other causes associated with systemic diseases. The most frequent systemic disease was juvenile idiopathic arthritis (20.0%), frosted form-associated uveitis (10.7%), followed by Behcet disease (10.7%), HLA B27-associated uveitis (2.7%), and Vogt-Koyanagi-Harada disease (2.7%). Complications occurred in 78.8% of affected eyes. The most common complications were posterior synechia (41.3%), cataract (18.7%), glaucoma (21.3%), and cystoid macular edema (20.0%).
2026-04-22 | Efficacy and safety of Jiawei Simiaoyongan granules in the treatment of non-infectious anterior uveitis: a randomized open-label trial.
To observe the clinical efficacy and safety of Chinese herbal medicine Jiawei Simiao Yongan granules (, JWSMYAG) in the treatment of non-infectious anterior uveitis (NIAU). We conducted a single-center, randomized, open-labeled clinical trial in adults with NIAU. Patients received standard treatment or a combination of JWSMYAG (twice daily) for three months, with a 3-month withdrawal period for observation. The primary endpoint was the recurrence rate within six months. A total of 98 patients were included in the intention-to-treat analysis, including 49 patients in the Traditional Chinese Medicine (TCM) group and 49 patients in the control group. Compared with the control group, the number of relapses was significantly lower in the TCM group [24.5% vs6.1%, P = 0.0224; Hazard Ratio = 0.208, 95% Confidence Interval (0.059, 0.737)]; in addition, patients in the TCM group had lower symptom scores of eye pain, insomnia, and bitter taste within two weeks (all P < 0.05). There was no significant difference between the two groups in terms of the difference in best corrected visual acuity change over six months, the number of intraocular pressure elevations > 10 mm Hg, the scoring of anterior chamber cells, the number of patients with keratic precipitates (+) after 1/2 weeks of treatment, and the scores of conjunctival hyperemia, headache, photophobia, and lacrimation. The difference in the number of adverse events between the two groups over six months was not statistically significant. JWSMYAG can reduce the recurrence rate of NIAU, alleviate ocular pain, insomnia, and bitter taste symptoms in patients with NIAU, and have a favorable safety profile.
2026-02-13 | Clinical effectiveness of the 0.18 mg fluocinolone acetonide intravitreal implant for non-infectious uveitis-associated macular edema: a real-world study.
OBJECTIVE: To evaluate the real-world clinical effectiveness and safety of the 0.18 mg fluocinolone acetonide intravitreal implant (FAi) in Chinese patients with macular edema (ME) secondary to non-infectious uveitis (NIU). METHODS: This single-center, retrospective case series included patients diagnosed with NIU-associated ME who received an intravitreal 0.18 mg FAi injection between January and September, 2024 and completed at least 12 months of follow-up. Primary outcome measures were changes in best-corrected visual acuity (BCVA, converted to logMAR), intraocular pressure (IOP), central macular thickness (CMT), and subfoveal choroidal thickness (SFCT) from baseline to 1, 3, 6, and 12 months post-treatment, analyzed using a linear mixed model. Inflammatory recurrence and treatment-related adverse events were also documented. RESULTS: A total of 39 patients (50 eyes) were included, with a mean age of 54.6 ± 14.8 years. The mean baseline BCVA was 0.65 ± 0.33 logMAR, and the mean CMT was 333.4 ± 108.6 μm. BCVA demonstrated significant improvement at all postoperative time points compared to baseline (all P< 0.001), reaching 0.48 ± 0.31 logMAR at 12 months. CMT showed a significant and sustained reduction postoperatively (all P< 0.001), decreasing to 239.7 ± 54.4 μm at 12 months. SFCT also decreased significantly from baseline (all P< 0.001). Postoperative IOP was significantly higher than baseline (P= 0.008, P= 0.001, P< 0.001, P< 0.001). Postoperative IOP elevation was observed in 18 eyes (36%). Management strategies included topical anti-glaucoma medication in 12 eyes and laser therapy in 3 eyes (1 selective laser trabeculoplasty and 2 diode laser cyclophotocoagulation). Notably, 3 eyes (6%) required trabeculectomy due to uncontrolled IOP. The inflammation recurrence rate during the 12-month follow-up was 14% (7/50 eyes). Implant migration into the anterior chamber occurred in one eye. No other serious ocular complications or systemic adverse events were observed. CONCLUSION: In this real-world study, the 0.18 mg FAi effectively improved visual acuity, reduced ME, and attenuated choroidal thickening in Chinese patients with NIU-associated ME over 12 months. The primary risk was manageable IOP elevation, resulting in an overall favorable safety profile. The 0.18 mg FAi represents an effective long-term treatment option for this patient population.
2026-01-31 | Iris Mass associated with Anterior Uveitis in Healthy Individuals: A Case Series
Iris mass associated with anterior uveitis is an uncommon finding and can be of various etiology. This study reports a unique approach to such cases and highlights the role of anti-fungal therapy. A series of three cases of iris mass with anterior uveitis, treated with anti-fungal therapy were retrospectively compiled. The first two cases were initially treated as non-infectious uveitis with corticosteroid, resulting in worsening of symptoms. Despite negative fungal microbiology, they were successfully treated with anti-fungal therapy. The third case with a similar clinical picture, without prior treatment, was effectively treated based on evidence from the other two cases. Any iris mass with uveitis needs proper clinical assessment and workup. Use of steroids, especially systemic, for any intraocular inflammation should be with caution.
gene therapies
2026-02-23 | Viral triggers and genetic predisposition in ocular autoimmunity: unraveling the breakdown of immune privilege and advancing targeted therapeutics.
The eye maintains vision through a distinctive immune privilege, utilizing physical barriers and active immunosuppression mediated by molecules such as FasL and PD-L1, as well as cells, including regulatory T cells and RPE cells. The emergence of sight-threatening immune-mediated ocular diseases, including non-infectious uveitis, signifies a significant disruption of this tolerance. This review analyzes the role of viral triggers and genetic predisposition in inducing immunological failure, while emphasizing the development of targeted therapeutic strategies. Viruses induce autoimmunity through molecular mimicry (Rotavirus peptides cross-reacting with retinal S-antigen), bystander activation, and active immune suppression (CMV inhibiting RPE cell IDO1 activity). HLA alleles, especially HLA-A29 (Birdshot Chorioretinopathy) and HLA-B27 (acute anterior uveitis), as well as non-MHC genes like NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and AIRE, greatly increase the risk of genetic disorders. Treatment is progressing towards precision medicine, with targeted biologics like the IL-6 receptor inhibitor Tocilizumab being key strategies. Moreover, AAV-mediated gene therapy that expresses immunosuppressive molecules such as HLA-G demonstrates promise for the restoration of long-term tolerance in preclinical models, facilitating the development of advanced future strategies.
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.
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.
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.
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].
antibodies
2026-05-30 | Clinical outcomes of weekly adalimumab in refractory non-infectious paediatric uveitis and the role of serum drug levels and anti-adalimumab antibodies.
Adalimumab (ADA) is a well-established treatment for refractory paediatric uveitis; however, some patients remain inadequately controlled on standard biweekly dosing. Weekly ADA injections are increasingly used, though evidence in paediatric cohorts remains limited. This study evaluates outcomes of escalation to weekly ADA in children with refractory uveitis and explores the relevance of serum drug levels and anti-ADA antibodies (AAA). Patients with idiopathic uveitis at two tertiary centres in the UK treated with weekly adalimumab were retrospectively reviewed. Demographic, clinical and laboratory data were collected, including age at escalation, systemic diagnosis, serum ADA levels, AAA titres pre- and post-escalation, clinical response and complications. Treatment success was defined as ≤0.5+ anterior chamber cells and <2 drops/day of steroid eye drops at 3 months, or most recent follow-up where escalation occurred within 3 months of review. 15 patients were included. Mean age at escalation was 11 years (range: 3-17). 11 (73%) had a systemic diagnosis; most commonly juvenile idiopathic arthritis (60%). Median serum level pre-escalation was 10.1 mg/L (IQR: 7.8-11.9) and 18.1 mg/L (IQR: 14.8-22.1) post escalation. AAAs were detectable in 7/15 (47%) pre-escalation, 2/15 (13.3%) post-escalation. Success occurred in 10/15 (67%), with visual acuity stable and improved in 93%. No serious systemic adverse events were reported. Weekly ADA offers a safe and effective treatment alternative for children with refractory uveitis, including those with AAAs. These findings support its inclusion in future treatment pathways, though the predictive value of serum levels and AAAs remains uncertain and warrants further investigation.
2026-05-04 | Model-Based Design of Sustained-Release Formulations of Anti-TNF-α Monoclonal Antibodies for Intravitreal Administration.
Background/Objectives: While intravitreal administration allows for increased ocular exposure to anti-TNF-α monoclonal antibodies, there is still a need for developing delivery systems able to prolong ocular drug exposure and alleviate patient compliance and safety concerns because of repeated injections. Therefore, the objective of this work was to guide the design of sustained-release formulations of anti-TNF-α monoclonal antibodies for intravitreal administration through a model-based strategy in non-infectious uveitis in the preclinical setting. Methods: Using an in-house-developed anterior uveitis disease model in rats, an intravenous reference dose reducing free TNF-α by 90% at the biophase was established. Intravitreal administrations of sustained-release formulations every 24 weeks were then simulated for adalimumab, golimumab and infliximab to evaluate TNF-α kinetics in the anterior chamber of the eye at different release rates. The selected sustained-release formulation was further evaluated for possible formulation issues causing device emptying before the next administration. Results: Intravitreal administration of sustained-release formulations releasing adalimumab, golimumab or infliximab at 1.802, 0.979 and 1.442 μg/week, respectively, met the predefined criteria of ≥90% reduction in free TNF-α at the biophase. TNF-α levels in aqueous humour were anticipated to be the most sensitive to detect possible formulation issues. Formulation emptying 10, 4 or 8 weeks for adalimumab, golimumab and infliximab, respectively, before next administration triggered TNF-α reaching pathological levels at week 24 post-dose. Conclusions: This work underscores the potential of new approach methodologies in the preclinical drug development of sustained-release formulations for intravitreal administration in ocular inflammatory disorders with less animal testing and without compromising the accuracy of model-informed predictions for human translation.
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.
2025-05-09 | Treatment outcomes of a Swiss non-infectious paediatric uveitis cohort: retrospective study over ten years.
Paediatric uveitis treatment recommendations suggest a step-up treatment approach starting with topical treatment, followed by antimetabolites and thereafter biologics. With this study, we are investigating the safety and efficacy of the current treatment approach in a large cohort. Single center retrospective study. Patients with non-infectious uveitis under the age of 18 years at first presentation, between January 2012 and June 2022, were eligible for inclusion. Data extracted from the electronic health records included age at first presentation, sex, involved eye segment, visual acuity (VA), complications, associated systemic disease, treatments, and number of consultations. Cases were grouped according to their final treatment regime (topical only, methotrexate, TNF alpha inhibitor, other). VA outcome, treatment response, adverse events, and frequency of consultations were evaluated. The study was approved by the local ethics committee. 64 non-infectious paediatric uveitis cases were included. Age at first diagnosis ranged from 2 to 17 years, with a two-peak distribution, 52% were male. Anterior uveitis was the most common presentation, followed by intermediate uveitis, posterior uveitis, and panuveitis. Topical treatment achieved remission in 23%, anti-metabolites in 12%, and escalation to TNF alpha inhibitors in 30%. Alternative treatments or observation only were documented in 16% and 17%, respectively. Median duration from first presentation to the start of anti-metabolite or TNF alpha inhibitor were 115 days and 269 days, respectively. There was a median of eight consultations during the first year of follow up. Frequency of consultations during the first year increased with every treatment escalation. VA outcome did not differ between the different treatment groups. The step-up treatment approach shows a safe profile in regards to VA outcome. Methotrexate presents a high rate of treatment failure and adverse effects. Adalimumab and infliximab are effective and safe. Timely treatment escalation might lower treatment burden for affected children, their families, and health care providers.
2025-03-14 | Secukinumab in refractory non-infectious anterior uveitis.
Secukinumab is a monoclonal antibody that selectively neutralizes interleukin-17A and has shown efficacy in the treatment of psoriatic arthritis, psoriasis, and axial spondyloarthritis. Its use in non-anterior non-infectious uveitis is controversial, with evidence generally not supporting its effectiveness in these conditions. However, the role of secukinumab in anterior non-infectious uveitis remains unclear. Case series. Five patients with biological therapy-refractory non-infectious anterior uveitis who were treated with secukinumab were included. All 5 patients experienced a uveitis flare-up during treatment, and secukinumab failed to induce long-term remission in 2 of these patients, who also had uncontrolled systemic disease. Secukinumab failed to prevent uveitis flare-up in these patients with biological therapy-refractory disease. Further studies are necessary to determine the potential role of secukinumab in the treatment of anterior uveitis.
other
2025-05-12 | Tissue resident memory T cells populate the human uveal tract
The current concept is that the eye is an immune privileged site endowed with innate immune regulatory networks to maintain organ function. We now have evidence that resident T cells occupy intraocular tissues. In immune-mediated inflammatory diseases, such as psoriasis and rheumatoid arthritis, tissue resident T cells trigger disease flares in the skin and joints. This suggests resident T cells in the uvea may have similar functions in non-infectious immune-mediated uveitis, a collective term for autoinflammatory and autoimmune diseases of the uveal tract causing intraocular inflammation. Here, we demonstrate by spectral cytometry and immunofluorescence imaging that non-inflamed uveal tissue contains multiple T cell subtypes including CD8+ CD103+ tissue resident memory T (TRM) cells. Using single cell RNA & T cell receptor (TCR) sequencing to profile aqueous humour cells from donors with acute, active uveitis, we identify clonally expanded T cells which are enriched for TRM -associated genes. We further show that in donors with active uveitis, CD8+ CD103+ T cells persist within tissue in the uveal tract. Using bulk RNA sequencing and weighted gene co-expression network analysis (WGCNA) we show that quiescent iris tissue from donors with a history of uveitis are enriched for genes associated with T cell activation and antigen presentation. Finally, we demonstrate that TRM cells persist in the anterior uvea in mice following resolution of experimental autoimmune uveoretinitis (EAU). Our results show that the human eye contains T cells both in health and during active inflammation. Our findings challenge the dogma that the eye is devoid of lymphocytes and supports the concept of resident T cell involvement in the pathogenesis of non-infectious immune-mediated uveitis and as promising targets for therapy.
2018-04-02 | Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell–Derived Retinal Pigment Epithelial Cells
Purpose: To determine whether human induced pluripotent stem (iPS) cell–derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation. Methods: iPS-RPE cells were cocultured with peripheral blood mononuclear cells (PBMCs) or purified NK cells from healthy donors after stimulation with cytokines. To confirm expression of NK cell–specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) were performed. NK cells (or PBMCs) cocultured with iPS-RPE cells were assessed for proliferation by Ki-67 expression with flow cytometry, and NK suppression by RPE cells was assessed for granzyme B production with ELISA. Human leukocyte antigen (HLA) expression including HLA-E on iPS-RPE cells was evaluated with flow cytometry and qRT-PCR. The effect of HLA-E downregulation was also investigated using small interfering RNA (siRNA) systems. Following iPS-RPE cell transplantation in vivo, we evaluated NK cell invasion in the retina with immunohistochemistry. Results: Activated NK cells expressed NK-related markers such as CD16, CD56, and CD11b, and NK cells produced cytotoxic agents such as granzyme B, perforin, and TNF-α. Human iPS-RPE cells inhibited cell proliferation and production of these cytotoxic agents by activated NK cells in vitro. iPS-RPE cells constitutively expressed HLA-E and suppressed NK cell activation through an interaction between HLA-E and CD94/NKG2A. Moreover, immunohistochemical evaluation of monkey RPE transplantation into in vivo immune rejection models showed no NK cell invasion in the retina in allografts or xenografts except for one xenografted eye. Conclusions: Cultured iPS cell–derived RPE cells greatly suppress NK cell activation. Thus, NK cells might be inactivated when exposed to this type of retinal cell.
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.
proteins
2024-10-25 | Efficacy and tolerability of subcutaneous repository corticotropin injection in refractory ocular inflammatory diseases.
Repository corticotropin injection (RCI) has been suggested to exert immunomodulatory and anti-inflammatory effects in ocular inflammation. The index retrospective study aimed to evaluate the efficacy and tolerability of subcutaneous RCI in patients with active scleritis or uveitis. Medical records of patients who were diagnosed with different types of active scleritis or uveitis and received RCI for more than six months at a tertiary eye center were reviewed. Patient characteristics including age, sex, comorbidities, clinical findings, treatment details, and adverse events were recorded. A total of 17 eyes of 17 patients were included. Median age was 43 years old and 53% of patients were male. Mean treatment duration was 25.4 ± 15.5 months. Indications for RCI therapy were scleritis (7 anterior and 1 posterior) (47.8%), panuveitis (17.4%), retinal vasculitis (17.4%), chronic/recurrent anterior uveitis (13%), and posterior uveitis (4.35%). RCI was initiated at a dose of 40 to 80 units 3 times weekly. Given the adequate control of inflammation, RCI was successfully discontinued in four patients (23.5%). Prior to RCI therapy, 14 (82.3%) patients were on oral prednisone at an average of 10 mg daily (range 2.5-40 mg), and two (11.7%) patients discontinued prednisone immediately before initiating RCI due to side effects. After six months of therapy, the prednisone dose was reduced in four (23.5%) patients to an average of 3 mg daily (range 1-5 mg) and was stopped in eight (53%) patients. Concomitant immunomodulatory therapies (IMTs) included mycophenolate mofetil (23.5%) and methotrexate (23.5%), and adalimumab (23.5%). Ten patients were on IMTs prior to using RCI, and during the course of treatment, IMT was stopped in two patients and reduced in one. Side effects included insomnia (23%), hypertension (11.7%), lower extremity edema (11.7%), hyperglycemia (11.7%), weight gain (11.7%), and infection (5.8%). RCI may be considered as a potential therapy with acceptable tolerability for patients with non-infectious scleritis or uveitis.
2023-09-01 | Targeted delivery of autoantigen to dendritic cells prevents development of spontaneous uveitis
Restoration of immunological tolerance to self antigens has been a major drive in understanding the mechanisms of, and developing new treatments for, autoimmune and autoinflammatory disease. Sessile dendritic cells (DC) are considered the main instruments underpinning immunological tolerance particularly the CD205+ (DEC205+) cDC1 subset in contrast to DCIR2+ cDC2 which mediate immunogenicity. Targeting DC using autoantigen peptide-antibody fusion proteins has been a well explored methodology for inducing tolerance. Here we show that subcutaneous (s.c.) inoculation of hen-egg lysozyme (HEL)-DEC205 Ig fusion prevents the development of spontaneous uveoretinitis (experimental autoimmune uveoretinitis, EAU) in a transgenic mouse model generated by crossing interphotoreceptor retinol binding protein (IRBP)-HEL (sTg HEL) with HEL specific TCR (sTg TCR) mice. Prolonged suppression of EAU required injections of HEL-DEC205 Ig once weekly, reflecting the half life of s.c. DC. Interestingly, HEL-DCIR2 Ig also had a suppressive effect on development of EAU but less so than DEC205 Ig while it had minimal effect on preventing the retinal atrophy associated with EAU. In addition, HEL-DEC205 Ig was only effective when administered s.c. rather than systemically and had no effect on EAU induced by adoptive transfer of HEL-activated T cells. These data demonstrate the importance of systemic (lymph node) rather than local (eye) antigen presentation in the development of EAU as well as suggest a potential therapeutic approach to controlling sight-threatening immune-mediated uveitis provided relevant antigen(s) can be identified.
2023-07-10 | The multifunctional human ocular melanocortin system.
Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells. α-MSH functions by binding to and activating melanocortin receptors (MC1R to MC5R) and receptor accessory proteins (MRAPs) that work in concert with antagonists, otherwise known as the melanocortin system. As well as controlling immune responses and inflammation, a broad range of biological functions is increasingly recognised to be orchestrated by the melanocortin system within ocular tissues. This includes maintaining corneal transparency and immune privilege by limiting corneal (lymph)angiogenesis, sustaining corneal epithelial integrity, protecting corneal endothelium and potentially enhancing corneal graft survival, regulating aqueous tear secretion with implications for dry eye disease, facilitating retinal homeostasis via maintaining blood-retinal barriers, providing neuroprotection in the retina, and controlling abnormal new vessel growth in the choroid and retina. The role of melanocortin signalling in uveal melanocyte melanogenesis however remains unclear compared to its established role in skin melanogenesis. The early application of a melanocortin agonist to downregulate systemic inflammation used adrenocorticotropic hormone (ACTH)-based repository cortisone injection (RCI), but adverse side effects including hypertension, edema, and weight gain, related to increased adrenal gland corticosteroid production, impacted clinical uptake. Compared to ACTH, melanocortin peptides that target MC1R, MC3R, MC4R and/or MC5R, but not adrenal gland MC2R, induce minimal corticosteroid production with fewer adverse systemic effects. Pharmacological advances in synthesising MCR-specific targeted peptides provide further opportunities for treating ocular (and systemic) inflammatory diseases. Following from these observations and a renewed clinical and pharmacological interest in the diverse biological roles of the melanocortin system, this review highlights the physiological and disease-related involvement of this system within human eye tissues. We also review the emerging benefits and versatility of melanocortin receptor targeted peptides as non-steroidal alternatives for inflammatory eye diseases such as non-infectious uveitis and dry eye disease, and translational applications in promoting ocular homeostasis, for example, in corneal transplantation and diabetic retinopathy.
2020-09-25 | Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema
Purpose: To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME). Methods: Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) >300 μm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1, IL-6, IL-8, IL-17, MCP-1, TNF-, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3+CD4+FoxP3+ in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels. Results: Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67; CI 95% (0.45-1.00); p = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, C I95%, 1.12-2.56, p = 0.049). Conclusions: Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.
2019-12-23 | A Cell Penetrating Peptide from Type I Interferon Protects the Retina in a Mouse Model of Autoimmune Uveitis
Abstract Experimental autoimmune uveitis (EAU) in rodents recapitulates many features of the disease in humans and has served as a useful tool for the development of therapeutics. A peptide from C-terminus of interferon α1, conjugated to palmitoyl-lysine for cell penetration, denoted as IFNα–C, was tested for its anti-inflammatory properties in ARPE-19 cells, followed by testing in a mouse model of EAU. Treatment with IFNα–C and evaluation by RT-qPCR showed the induction of anti-inflammatory cytokines and chemokine. Inflammatory markers induced by treatment with TNFα were suppressed when IFNα–C was simultaneously present. TNF-α mediated induction of NF-kB and signaling by IL-17A were attenuated by IFNα–C. Differentiated ARPE-19 cells were treated with TNFα in the presence or absence IFNα–C and analyzed by immmunhistochemistry. IFNα–C protected against the disruption integrity of tight junction proteins. Similarly, loss of transepithelial resistance caused by TNFα was prevented by IFNα–C. B10.RIII mice were immunized with a peptide from interphotoreceptor binding protein (IRBP) and treated by gavage with IFNα–C. Development of uveitis was monitored by histology, fundoscopy, SD-OCT, and ERG. Treatment with IFNα–C prevented uveitis in mice immunized with the IRBP peptide. Splenocytes isolated from mice with ongoing EAU exhibited antigenspecific T cell proliferation that was inhibited in the presence of IFNα–C. IFNα–C peptide exhibits anti-inflammatory properties and protects mice against damage to retinal structure and function suggesting that it has therapeutic potential for the treatment of autoimmune uveitis.
small molecules
2026-05-23 | Epidemiology and outcomes of non-infectious paediatric uveitis in the French Caribbean: a 15-year cohort study from a high-income health system in Martinique.
Non-infectious uveitis (NIU) are rare in children but might be associated with substantial visual impairment. Most NIU paediatric cohorts originate from Europe, North America, or Asia, with minimal representation of Caribbean populations. Our study aimed to describe the epidemiology, clinical features, aetiologies and outcomes of paediatric NIU in Martinique. We conducted a monocentre, retrospective cohort study that included all children under the age of 18 diagnosed with NIU at the University Hospital of Martinique between 2010 and 2024. We identified cases through paediatric and ophthalmology registries, medical records, and national hospital databases. We excluded infectious uveitis and non-residents. Incidence estimates used population data. A total of 17 children with NIU were included in the study. 41% were male, with a mean age at diagnosis of 8.7 years (range: 2.5-16) and a median follow-up period of 7.6 years (range: 2.2-11.6). Eleven patients had anterior uveitis (64.7%), and 35.3% had panuveitis. Uveitis was unilateral in 64.7% of patients. The estimated incidence was 1.4 per 100,000 person-years (95% CI 0.83-2.27). The leading aetiology was juvenile idiopathic arthritis, accounting for 58.8% of cases. Systemic biologics were used in 17.6% of patients. Only one child experienced visual loss and required ocular surgery at the final follow-up. The first Caribbean paediatric NIU cohort shows a similar etiological spectrum and good visual outcomes as reported in high-income countries.
2026-04-29 | Demographic and clinical pattern of non-infectious uveitis in the Tripoli Children's Hospital
Uveitis is relatively rare in the pediatric population, but it leads to considerable ocular morbidity. This study aims to describe the clinical, etiological, and treatment features of noninfectious uveitis in Libyan children in a pediatric rheumatology clinic. A retrospective analysis of medical records of pediatric patients who were diagnosed with noninfectious uveitis from January 2000 to December 2021 at the pediatric rheumatology clinic at Tripoli Children's Hospital, Tripoli, Libya, was conducted. All the cases of uveitis in patients under 18 years of age at diagnosis were included. The collected data included age at diagnosis, anatomical location of uveitis, laterality, associated systemic disease, used medications, and visual outcome. 75 patients (137 eyes) comprised the study sample. The mean age at the onset of uveitis was 8.9 ± 3.5 years. The female-to-male ratio was 1: 1.7. Pan uveitis was the most frequent anatomical location (54.7%), followed by anterior uveitis (36.0%), posterior (8.0%), and intermediate (1.3%). The bilateral eye was involved in 82.7%, and the unilateral eye was involved in 17.3%. The common causes of non-infectious uveitis are chronic idiopathic (52.0%), which was the most frequent etiology. Other causes associated with systemic diseases. The most frequent systemic disease was juvenile idiopathic arthritis (20.0%), frosted form-associated uveitis (10.7%), followed by Behcet disease (10.7%), HLA B27-associated uveitis (2.7%), and Vogt-Koyanagi-Harada disease (2.7%). Complications occurred in 78.8% of affected eyes. The most common complications were posterior synechia (41.3%), cataract (18.7%), glaucoma (21.3%), and cystoid macular edema (20.0%).
2026-04-22 | Efficacy and safety of Jiawei Simiaoyongan granules in the treatment of non-infectious anterior uveitis: a randomized open-label trial.
To observe the clinical efficacy and safety of Chinese herbal medicine Jiawei Simiao Yongan granules (, JWSMYAG) in the treatment of non-infectious anterior uveitis (NIAU). We conducted a single-center, randomized, open-labeled clinical trial in adults with NIAU. Patients received standard treatment or a combination of JWSMYAG (twice daily) for three months, with a 3-month withdrawal period for observation. The primary endpoint was the recurrence rate within six months. A total of 98 patients were included in the intention-to-treat analysis, including 49 patients in the Traditional Chinese Medicine (TCM) group and 49 patients in the control group. Compared with the control group, the number of relapses was significantly lower in the TCM group [24.5% vs6.1%, P = 0.0224; Hazard Ratio = 0.208, 95% Confidence Interval (0.059, 0.737)]; in addition, patients in the TCM group had lower symptom scores of eye pain, insomnia, and bitter taste within two weeks (all P < 0.05). There was no significant difference between the two groups in terms of the difference in best corrected visual acuity change over six months, the number of intraocular pressure elevations > 10 mm Hg, the scoring of anterior chamber cells, the number of patients with keratic precipitates (+) after 1/2 weeks of treatment, and the scores of conjunctival hyperemia, headache, photophobia, and lacrimation. The difference in the number of adverse events between the two groups over six months was not statistically significant. JWSMYAG can reduce the recurrence rate of NIAU, alleviate ocular pain, insomnia, and bitter taste symptoms in patients with NIAU, and have a favorable safety profile.
2026-02-13 | Clinical effectiveness of the 0.18 mg fluocinolone acetonide intravitreal implant for non-infectious uveitis-associated macular edema: a real-world study.
OBJECTIVE: To evaluate the real-world clinical effectiveness and safety of the 0.18 mg fluocinolone acetonide intravitreal implant (FAi) in Chinese patients with macular edema (ME) secondary to non-infectious uveitis (NIU). METHODS: This single-center, retrospective case series included patients diagnosed with NIU-associated ME who received an intravitreal 0.18 mg FAi injection between January and September, 2024 and completed at least 12 months of follow-up. Primary outcome measures were changes in best-corrected visual acuity (BCVA, converted to logMAR), intraocular pressure (IOP), central macular thickness (CMT), and subfoveal choroidal thickness (SFCT) from baseline to 1, 3, 6, and 12 months post-treatment, analyzed using a linear mixed model. Inflammatory recurrence and treatment-related adverse events were also documented. RESULTS: A total of 39 patients (50 eyes) were included, with a mean age of 54.6 ± 14.8 years. The mean baseline BCVA was 0.65 ± 0.33 logMAR, and the mean CMT was 333.4 ± 108.6 μm. BCVA demonstrated significant improvement at all postoperative time points compared to baseline (all P< 0.001), reaching 0.48 ± 0.31 logMAR at 12 months. CMT showed a significant and sustained reduction postoperatively (all P< 0.001), decreasing to 239.7 ± 54.4 μm at 12 months. SFCT also decreased significantly from baseline (all P< 0.001). Postoperative IOP was significantly higher than baseline (P= 0.008, P= 0.001, P< 0.001, P< 0.001). Postoperative IOP elevation was observed in 18 eyes (36%). Management strategies included topical anti-glaucoma medication in 12 eyes and laser therapy in 3 eyes (1 selective laser trabeculoplasty and 2 diode laser cyclophotocoagulation). Notably, 3 eyes (6%) required trabeculectomy due to uncontrolled IOP. The inflammation recurrence rate during the 12-month follow-up was 14% (7/50 eyes). Implant migration into the anterior chamber occurred in one eye. No other serious ocular complications or systemic adverse events were observed. CONCLUSION: In this real-world study, the 0.18 mg FAi effectively improved visual acuity, reduced ME, and attenuated choroidal thickening in Chinese patients with NIU-associated ME over 12 months. The primary risk was manageable IOP elevation, resulting in an overall favorable safety profile. The 0.18 mg FAi represents an effective long-term treatment option for this patient population.
2026-01-31 | Iris Mass associated with Anterior Uveitis in Healthy Individuals: A Case Series
Iris mass associated with anterior uveitis is an uncommon finding and can be of various etiology. This study reports a unique approach to such cases and highlights the role of anti-fungal therapy. A series of three cases of iris mass with anterior uveitis, treated with anti-fungal therapy were retrospectively compiled. The first two cases were initially treated as non-infectious uveitis with corticosteroid, resulting in worsening of symptoms. Despite negative fungal microbiology, they were successfully treated with anti-fungal therapy. The third case with a similar clinical picture, without prior treatment, was effectively treated based on evidence from the other two cases. Any iris mass with uveitis needs proper clinical assessment and workup. Use of steroids, especially systemic, for any intraocular inflammation should be with caution.
gene therapies
2026-02-23 | Viral triggers and genetic predisposition in ocular autoimmunity: unraveling the breakdown of immune privilege and advancing targeted therapeutics.
The eye maintains vision through a distinctive immune privilege, utilizing physical barriers and active immunosuppression mediated by molecules such as FasL and PD-L1, as well as cells, including regulatory T cells and RPE cells. The emergence of sight-threatening immune-mediated ocular diseases, including non-infectious uveitis, signifies a significant disruption of this tolerance. This review analyzes the role of viral triggers and genetic predisposition in inducing immunological failure, while emphasizing the development of targeted therapeutic strategies. Viruses induce autoimmunity through molecular mimicry (Rotavirus peptides cross-reacting with retinal S-antigen), bystander activation, and active immune suppression (CMV inhibiting RPE cell IDO1 activity). HLA alleles, especially HLA-A29 (Birdshot Chorioretinopathy) and HLA-B27 (acute anterior uveitis), as well as non-MHC genes like NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and AIRE, greatly increase the risk of genetic disorders. Treatment is progressing towards precision medicine, with targeted biologics like the IL-6 receptor inhibitor Tocilizumab being key strategies. Moreover, AAV-mediated gene therapy that expresses immunosuppressive molecules such as HLA-G demonstrates promise for the restoration of long-term tolerance in preclinical models, facilitating the development of advanced future strategies.
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.
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.
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.
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].
antibodies
2026-05-30 | Clinical outcomes of weekly adalimumab in refractory non-infectious paediatric uveitis and the role of serum drug levels and anti-adalimumab antibodies.
Adalimumab (ADA) is a well-established treatment for refractory paediatric uveitis; however, some patients remain inadequately controlled on standard biweekly dosing. Weekly ADA injections are increasingly used, though evidence in paediatric cohorts remains limited. This study evaluates outcomes of escalation to weekly ADA in children with refractory uveitis and explores the relevance of serum drug levels and anti-ADA antibodies (AAA). Patients with idiopathic uveitis at two tertiary centres in the UK treated with weekly adalimumab were retrospectively reviewed. Demographic, clinical and laboratory data were collected, including age at escalation, systemic diagnosis, serum ADA levels, AAA titres pre- and post-escalation, clinical response and complications. Treatment success was defined as ≤0.5+ anterior chamber cells and <2 drops/day of steroid eye drops at 3 months, or most recent follow-up where escalation occurred within 3 months of review. 15 patients were included. Mean age at escalation was 11 years (range: 3-17). 11 (73%) had a systemic diagnosis; most commonly juvenile idiopathic arthritis (60%). Median serum level pre-escalation was 10.1 mg/L (IQR: 7.8-11.9) and 18.1 mg/L (IQR: 14.8-22.1) post escalation. AAAs were detectable in 7/15 (47%) pre-escalation, 2/15 (13.3%) post-escalation. Success occurred in 10/15 (67%), with visual acuity stable and improved in 93%. No serious systemic adverse events were reported. Weekly ADA offers a safe and effective treatment alternative for children with refractory uveitis, including those with AAAs. These findings support its inclusion in future treatment pathways, though the predictive value of serum levels and AAAs remains uncertain and warrants further investigation.
2026-05-04 | Model-Based Design of Sustained-Release Formulations of Anti-TNF-α Monoclonal Antibodies for Intravitreal Administration.
Background/Objectives: While intravitreal administration allows for increased ocular exposure to anti-TNF-α monoclonal antibodies, there is still a need for developing delivery systems able to prolong ocular drug exposure and alleviate patient compliance and safety concerns because of repeated injections. Therefore, the objective of this work was to guide the design of sustained-release formulations of anti-TNF-α monoclonal antibodies for intravitreal administration through a model-based strategy in non-infectious uveitis in the preclinical setting. Methods: Using an in-house-developed anterior uveitis disease model in rats, an intravenous reference dose reducing free TNF-α by 90% at the biophase was established. Intravitreal administrations of sustained-release formulations every 24 weeks were then simulated for adalimumab, golimumab and infliximab to evaluate TNF-α kinetics in the anterior chamber of the eye at different release rates. The selected sustained-release formulation was further evaluated for possible formulation issues causing device emptying before the next administration. Results: Intravitreal administration of sustained-release formulations releasing adalimumab, golimumab or infliximab at 1.802, 0.979 and 1.442 μg/week, respectively, met the predefined criteria of ≥90% reduction in free TNF-α at the biophase. TNF-α levels in aqueous humour were anticipated to be the most sensitive to detect possible formulation issues. Formulation emptying 10, 4 or 8 weeks for adalimumab, golimumab and infliximab, respectively, before next administration triggered TNF-α reaching pathological levels at week 24 post-dose. Conclusions: This work underscores the potential of new approach methodologies in the preclinical drug development of sustained-release formulations for intravitreal administration in ocular inflammatory disorders with less animal testing and without compromising the accuracy of model-informed predictions for human translation.
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.
2025-05-09 | Treatment outcomes of a Swiss non-infectious paediatric uveitis cohort: retrospective study over ten years.
Paediatric uveitis treatment recommendations suggest a step-up treatment approach starting with topical treatment, followed by antimetabolites and thereafter biologics. With this study, we are investigating the safety and efficacy of the current treatment approach in a large cohort. Single center retrospective study. Patients with non-infectious uveitis under the age of 18 years at first presentation, between January 2012 and June 2022, were eligible for inclusion. Data extracted from the electronic health records included age at first presentation, sex, involved eye segment, visual acuity (VA), complications, associated systemic disease, treatments, and number of consultations. Cases were grouped according to their final treatment regime (topical only, methotrexate, TNF alpha inhibitor, other). VA outcome, treatment response, adverse events, and frequency of consultations were evaluated. The study was approved by the local ethics committee. 64 non-infectious paediatric uveitis cases were included. Age at first diagnosis ranged from 2 to 17 years, with a two-peak distribution, 52% were male. Anterior uveitis was the most common presentation, followed by intermediate uveitis, posterior uveitis, and panuveitis. Topical treatment achieved remission in 23%, anti-metabolites in 12%, and escalation to TNF alpha inhibitors in 30%. Alternative treatments or observation only were documented in 16% and 17%, respectively. Median duration from first presentation to the start of anti-metabolite or TNF alpha inhibitor were 115 days and 269 days, respectively. There was a median of eight consultations during the first year of follow up. Frequency of consultations during the first year increased with every treatment escalation. VA outcome did not differ between the different treatment groups. The step-up treatment approach shows a safe profile in regards to VA outcome. Methotrexate presents a high rate of treatment failure and adverse effects. Adalimumab and infliximab are effective and safe. Timely treatment escalation might lower treatment burden for affected children, their families, and health care providers.
2025-03-14 | Secukinumab in refractory non-infectious anterior uveitis.
Secukinumab is a monoclonal antibody that selectively neutralizes interleukin-17A and has shown efficacy in the treatment of psoriatic arthritis, psoriasis, and axial spondyloarthritis. Its use in non-anterior non-infectious uveitis is controversial, with evidence generally not supporting its effectiveness in these conditions. However, the role of secukinumab in anterior non-infectious uveitis remains unclear. Case series. Five patients with biological therapy-refractory non-infectious anterior uveitis who were treated with secukinumab were included. All 5 patients experienced a uveitis flare-up during treatment, and secukinumab failed to induce long-term remission in 2 of these patients, who also had uncontrolled systemic disease. Secukinumab failed to prevent uveitis flare-up in these patients with biological therapy-refractory disease. Further studies are necessary to determine the potential role of secukinumab in the treatment of anterior uveitis.
other
2025-05-12 | Tissue resident memory T cells populate the human uveal tract
The current concept is that the eye is an immune privileged site endowed with innate immune regulatory networks to maintain organ function. We now have evidence that resident T cells occupy intraocular tissues. In immune-mediated inflammatory diseases, such as psoriasis and rheumatoid arthritis, tissue resident T cells trigger disease flares in the skin and joints. This suggests resident T cells in the uvea may have similar functions in non-infectious immune-mediated uveitis, a collective term for autoinflammatory and autoimmune diseases of the uveal tract causing intraocular inflammation. Here, we demonstrate by spectral cytometry and immunofluorescence imaging that non-inflamed uveal tissue contains multiple T cell subtypes including CD8+ CD103+ tissue resident memory T (TRM) cells. Using single cell RNA & T cell receptor (TCR) sequencing to profile aqueous humour cells from donors with acute, active uveitis, we identify clonally expanded T cells which are enriched for TRM -associated genes. We further show that in donors with active uveitis, CD8+ CD103+ T cells persist within tissue in the uveal tract. Using bulk RNA sequencing and weighted gene co-expression network analysis (WGCNA) we show that quiescent iris tissue from donors with a history of uveitis are enriched for genes associated with T cell activation and antigen presentation. Finally, we demonstrate that TRM cells persist in the anterior uvea in mice following resolution of experimental autoimmune uveoretinitis (EAU). Our results show that the human eye contains T cells both in health and during active inflammation. Our findings challenge the dogma that the eye is devoid of lymphocytes and supports the concept of resident T cell involvement in the pathogenesis of non-infectious immune-mediated uveitis and as promising targets for therapy.
2018-04-02 | Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell–Derived Retinal Pigment Epithelial Cells
Purpose: To determine whether human induced pluripotent stem (iPS) cell–derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation. Methods: iPS-RPE cells were cocultured with peripheral blood mononuclear cells (PBMCs) or purified NK cells from healthy donors after stimulation with cytokines. To confirm expression of NK cell–specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) were performed. NK cells (or PBMCs) cocultured with iPS-RPE cells were assessed for proliferation by Ki-67 expression with flow cytometry, and NK suppression by RPE cells was assessed for granzyme B production with ELISA. Human leukocyte antigen (HLA) expression including HLA-E on iPS-RPE cells was evaluated with flow cytometry and qRT-PCR. The effect of HLA-E downregulation was also investigated using small interfering RNA (siRNA) systems. Following iPS-RPE cell transplantation in vivo, we evaluated NK cell invasion in the retina with immunohistochemistry. Results: Activated NK cells expressed NK-related markers such as CD16, CD56, and CD11b, and NK cells produced cytotoxic agents such as granzyme B, perforin, and TNF-α. Human iPS-RPE cells inhibited cell proliferation and production of these cytotoxic agents by activated NK cells in vitro. iPS-RPE cells constitutively expressed HLA-E and suppressed NK cell activation through an interaction between HLA-E and CD94/NKG2A. Moreover, immunohistochemical evaluation of monkey RPE transplantation into in vivo immune rejection models showed no NK cell invasion in the retina in allografts or xenografts except for one xenografted eye. Conclusions: Cultured iPS cell–derived RPE cells greatly suppress NK cell activation. Thus, NK cells might be inactivated when exposed to this type of retinal cell.
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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Drug Discovery Landscape
10 orphan drug designations for Non-infectious anterior uveitis.
10 orphan drug designations for Non-infectious anterior uveitis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Vamikibart | antibodies | EMA | 2025-04-16 | — | Roche Registration GmbH |
methotrexate | small molecules | FDA | 2023-10-04 | — | Nordic Group B.V. |
AAV2.adalimumab | antibodies | FDA | 2022-06-22 | — | Kriya Therapeutics, Inc. |
Fluocinolone acetonide [Uvisert] | small molecules | EMA | 2016-04-28 | — | Campharm Limited |
3-{[2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)biphenyl-4-yl]carbamoyl}thiophene-2-carboxylic acid | small molecules | EMA | 2015-06-19 | — | Kiora Pharmaceuticals GmbH |
Autologous collagen type II-specific regulatory T-cells [Col-Treg] | cell therapies | EMA | 2014-12-16 | — | Sangamo Therapeutics France S.A.S. |
Gevokizumab | antibodies | EMA | 2013-03-12 | — | Xoma UK Limited |
Voclosporin | small molecules | EMA | 2012-12-06 | — | Granzer Regulatory Consulting & Services GmbH |
gevokizumab | antibodies | FDA | 2012-08-20 | — | XOMA (US) LLC |
Sirolimus [Opsiria] | small molecules | EMA | 2011-08-30 | — | Santen Oy |
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