Phase 2 randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis

Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase 2 multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase 2 study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main Outcome Measures: Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK

Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis

Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK

Métalloproteinases matricielles et cicatrisation cornéenne (rôle D'EMMPRIN et des interactions epithélio-stromales)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Conjunctival and Limbal Conjunctival Autograft vs. Amniotic Membrane Graft in Primary Pterygium Surgery: A 30-Year Comprehensive Review

Abstract Introduction The purpose of this study is to compare the “real-life” effectiveness of amniotic membrane graft (AMG) and conjunctival (CAT) or limbal conjunctival (LCA) autograft in the management of primary pterygium. Methods Human-based studies on primary pterygium surgery that were published between 1993 and 2022 with at least 3 months of follow-up were identified, and only those that were retrospective were included. The global recurrence rate of pterygium was assessed for each surgical technique separately. Specific recurrence rates taking into consideration the fixation technique (glue versus sutures) were also measured. Results 35 real-life retrospective subgroups comprising a total of 3747 eyes were included in the final review. The mean global recurrence rates for CAT, LCA and AMG were 7.61%, 5.50% and 9.0%, respectively. Recurrences were less common for patients who received fibrin glue (5.92%, 2.56% and 3.60%) than for those who received sutures (8.99%, 6.03% and 23.0%) for the three groups, respectively. Surgical techniques combining CAT or LCA with AMG yielded an even lower global recurrence rate (1.83%). Conclusion AMG seems like a reasonable option that could be considered in primary pterygium surgery, especially when glued to the underlying sclera. Combining AMG with other treatment modalities such as CAT or LCA seems to offer an interesting alternative in terms of recurrence

Role of emmprin/CD147 in tissue remodeling.

Emmprin/CD147 is a cell membrane glycoprotein that belongs to the Ig superfamily and is involved in numerous physiological and pathological systems. Through its ability to interact with multiple partners within the cell surface and its potential to regulate the expression of several targets within the cell, emmprin may have different functions depending on the cell or tissue type. However, its role in tissue remodeling remains the most clearly demonstrated. Emmprin is able to induce, in the same cellular model, both the matrix metalloproteinases and the serine protease urokinase plasminogen activator, whose concerted action in the breakdown of the extracellular matrix (ECM) during various physiopathological situations has been reported. In addition, emmprin also promotes myofibroblasts' differentiation and tissue contraction through the induction of alpha smooth muscle actin, thus expanding on the mechanism by which emmprin remodels ECM

In Vivo Corneal Confocal Microscopy in Mucolipidosis Type IV

International audiencein Mucolipidosis Type IV A 7-year-old girl referred for a progressive bilateral visual impairment was found with a diffuse epithelial corneal infiltration appearing as small translucent vesicles (Fig A). Confocal microscopy showed hyperreflectivity of the cytoplasm of the superficial (Fig B) and basal corneal epithelial cells, making the nuclei more visible than in normal eyes (Fig C). This epithelial infiltration in a child of consanguineous union was suspicious for a lysosomal storage disease due to MCOLN1 mutation: mucolipidosis type IV. The skin biopsy confirmed this diagnosis, showing heterogeneous inclusions in the endothelial cells cytoplasm on electron microscopy (Fig D): multivesicular bodies (arrow), osmiophilic bodies (asterisks), and electron-empty vesicles (stars

Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions

Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor DDIT3 were markedly upregulated in patients with Sj&ouml;gren&rsquo;s dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of CXCL8 and IL5, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease

Kératoplasties transfixiantes en z assistées par laser femtoseconde (étude anatomo-clinique)

Avec près de 3000 interventions pratiquées chaque année en France, la kératoplastie transfixiante est une procédure qui bénéficie d un siècle d évolution. Depuis 2006, le chirurgien a la possibilité de pratiquer les trépanations à l aide du laser femtoseconde. Ce laser à impulsions ultracourtes permet des incisions cornéennes complexes, grâce au principe de photodisruption. L objectif de ce travail est de réaliser une étude anatomo-clinique sur une série de kératoplasties transfixiantes en Z assistées par laser femtoseconde. Cette étude rétrospective a concerné 15 patients opérés entre 2007 et 2009 à l Hôtel-Dieu de Paris. Un an après la chirurgie, l acuité visuelle moyenne a été mesurée à 0.45 logMar et l astigmatisme à 3.8D. L ablation du sujet a été réalisée à 6 mois dans 80% des cas. L étude histologique a mis en évidence une incision homogène, avec peu de lésions liées aux effets secondaires du laser. Les résultats fonctionnels de cette série ont été équivalents à ceux obtenus après trépanation mécanique. Les résultats histologiques corroborent ceux de la littérature, qui montrent que la découpe est de bonne qualité avec peu de dégâts tissulaires. La kératoplastie transfixiante assistée par laser femtoseconde représente une avancée chirurgicale mais n a pas démontré pour l instant sa supériorité par rapport au trépan mécanique. L absence d amélioration évidente et les contraintes exigées par la technique expliquent sa diffusion encore limitée. Des évolutions devront donc être réalisées, sur l autofocalisation et sur la longueur d onde des lasers, avant de s imposer comme technique de référenceWith around 3000 procedures carried out every year in france, penetrating keratoplasty has benefited from technical developments for one century. Since 2006, surgeon has the opportunity to practice trephinations with femtosecond laser. This ultra-short impulsions laser allows complex corneal incisions, thanks to the photodisruption principle. This work objective was to realise an anatomo-clinical study based on a series of pentrating keratoplasties zig-zag incision performed with femtosecond laser. This retrospective study has included 15 patients operated from 2007 to 2009 at Hôtel-Dieu hospital in paris. One year after surgery, the average visual acuity measured was 0.45 logMar and the astigmatism was 3.8D. Suture removing has been realised after 6 months in 80% of cases. The histological study showed an homogenic incision, with few lesions linked with secondary effects of the laser. Functional results of this series have been similar to those obtained after mechanical trephination. Histological results corroborated litterature ones, which showed that the cutting was highly qualitative and with rare tissue damages. Penetrating keratoplasty assisted by femtosecond laser represents a surgical advanced but has not proved at this time a real superiority compared to the mechanical trephine. The absence of any obvious improvement and the constraints required by this technique explained its limited spreading. Technical developments would have to be realised in the future, on the laser autofocalisation and wave-length, before being able to asert itself as a refering techniqueST QUENTIN EN YVELINES-BU (782972101) / SudocSudocFranceF