A Novel Combination Therapy Tß4/VIP Protects against Hyperglycemia-Induced Changes in Human Corneal Epithelial Cells.

Despite the prevalence of diabetic retinopathy, the majority of adult diabetic patients develop visually debilitating corneal complications, including impaired wound healing. Unfortunately, there is limited treatment for diabetes-induced corneal damage. The current project investigates a novel, peptide-based combination therapy, thymosin beta-4 and vasoactive intestinal peptide (Tß4/VIP), against high-glucose-induced damage to the corneal epithelium. Electric cell-substrate impedance sensing (ECIS) was used for real-time monitoring of barrier function and wound healing of human corneal epithelial cells maintained in either normal glucose (5 mM) or high glucose (25 mM) ± Tß4 (0.1%) and VIP (5 nM). Barrier integrity was assessed by resistance, impedance, and capacitance measurements. For the wound healing assay, cell migration was also monitored. Corneal epithelial tight junction proteins (ZO-1, ZO-2, occludin, and claudin-1) were assessed to confirm our findings. Barrier integrity and wound healing were significantly impaired under high-glucose conditions. However, barrier function and cell migration significantly improved with Tß4/VIP treatment. These findings were supported by high-glucose-induced downregulation of tight junction proteins that were effectively maintained similar to normal levels when treated with Tß4/VIP. These results strongly support the premise that Tß4 and VIP work synergistically to protect corneal epithelial cells against hyperglycemia-induced damage. In addition, this work highlights the potential for significant translational impact regarding the treatment of diabetic patients and associated complications of the cornea.

Thymosin beta 4: A potential novel adjunct treatment for bacterial keratitis.

Microbial keratitis is a rapidly progressing, visually debilitating infection of the cornea that can lead to corneal scarring, endophthalmitis, and perforation. Corneal opacification or scarring, a complication of keratitis, is among the leading causes of legal blindness worldwide, second to cataracts.Pseudomonas aeruginosaandStaphylococcus aureusare the two bacteria most commonly associated with this type of infection. Risk factors include patients who are immunocompromised, those who have undergone refractive corneal surgery, and those with prior penetrating keratoplasty, as well as extended wear contact lens users. Current treatment of microbial keratitis primarily addresses the pathogen using antibiotics. Bacterial clearance is of utmost importance yet does not guarantee good visual outcome. Clinicians are often left to rely upon the eye's innate ability to heal itself, as there are limited options beyond antibiotics and corticosteroids for treating patients with corneal infection. Beyond antibiotics, agents in use, such as lubricating ointments, artificial tears, and anti-inflammatory drops, do not fully accommodate clinical needs and have many potential harmful complications. To this end, treatments are needed that both regulate the inflammatory response and promote corneal wound healing to resolve visual disturbances and improve quality of life. Thymosin beta 4 is a small, naturally occurring 43-amino-acid protein that promotes wound healing and reduces corneal inflammation and is currently in Phase 3 human clinical trials for dry eye disease. Our previous work has shown that topical Tß4 as an adjunct to ciprofloxacin treatment reduces inflammatory mediators and inflammatory cell infiltrates (neutrophils/PMN and macrophages) while enhancing bacterial killing and wound healing pathway activation in an experimental model ofP. aeruginosa-induced keratitis. Adjunctive thymosin beta 4 treatment holds novel therapeutic potential to regulate and, optimally, resolve disease pathogenesis in the cornea and perhaps other infectious and immune-based inflammatory disease. We plan to establish the importance of thymosin beta 4 as a therapeutic agent in conjunction with antibiotics with high impact for immediate clinical development.

0.1% RGN-259 (Thymosin ß4) Ophthalmic Solution Promotes Healing and Improves Comfort in Neurotrophic Keratopathy Patients in a Randomized, Placebo-Controlled, Double-Masked Phase III Clinical Trial.

We determined the efficacy and safety of 0.1% RGN-259 ophthalmic solution (containing the regenerative protein thymosin ß4) in promoting the healing of persistent epithelial defects in patients with Stages 2 and 3 neurotrophic keratopathy. Complete healing occurred after 4 weeks in 6 of the 10 RGN-259-treated subjects and in 1 of the 8 placebo-treated subjects (p = 0.0656), indicating a strong efficacy trend. Additional efficacy was seen in the significant healing (p = 0.0359) with no recurrent defects observed at day 43, two weeks after cessation of treatment, while the one healed placebo-treated subject at day 28 suffered a recurrence at day 43. The Mackie classification disease stage improved in the RGN-259-treated group at Days 29, 36, and 43 (p = 0.0818, 0.0625, and 0.0467, respectively). Time to complete healing also showed a trend towards efficacy (p = 0.0829, Kaplan-Meier) with 0.1% RGN-259. RGN-259-treated subjects had significant improvements at multiple time points in ocular discomfort, foreign body sensation, and dryness which were not seen in the placebo group. No significant adverse effects were observed. In summary, the use of 0.1% RGN-259 promotes rapid healing of epithelial defects in neurotrophic keratopathy, improves ocular comfort, and is safe for treating this challenging population of patients.

Adjunctive Thymosin Beta-4 Treatment Influences PMN Effector Cell Function during Pseudomonas aeruginosa-Induced Corneal Infection.

Previous work examining the therapeutic efficacy of adjunct thymosin beta 4 (Tß4) to ciprofloxacin for ocular infectious disease has revealed markedly reduced inflammation (inflammatory mediators and innate immune cells) with increased activation of wound healing pathways. Understanding the therapeutic mechanisms of action have further revealed a synergistic effect with ciprofloxacin to enhance bacterial killing along with a regulatory influence over macrophage effector cell function. As a natural extension of the aforementioned work, the current study uses an experimental model of P. aeruginosa-induced keratitis to examine the influence of Tß4 regarding polymorphonuclear leukocyte (PMN/neutrophil) cellular function, contributing to improved disease response. Flow cytometry was utilized to phenotypically profile infiltrating PMNs after infection. The generation of reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and PMN apoptosis were investigated to assess the functional activities of PMNs in response to Tß4 therapy. In vitro work using peritoneal-derived PMNs was similarly carried out to verify and extend our in vivo findings. The results indicate that the numbers of infiltrated PMNs into infected corneas were significantly reduced with adjunctive Tß4 treatment. This was paired with the downregulated expression of proinflammatory markers on these cells, as well. Data generated from PMN functional studies suggested that the corneas of adjunctive Tß4 treated B6 mice exhibit a well-regulated production of ROS, NETs, and limited PMN apoptosis. In addition to confirming the in vivo results, the in vitro findings also demonstrated that neutrophil elastase (NE) was unnecessary for NETosis. Collectively, these data provide additional evidence that adjunctive Tß4 + ciprofloxacin treatment is a promising option for bacterial keratitis that addresses both the infectious pathogen and cellular-mediated immune response, as revealed by the current study.

Adjunctive Thymosin Beta-4 Treatment Influences MΦ Effector Cell Function to Improve Disease Outcome in Pseudomonas aeruginosa-Induced Keratitis.

Our previous work has shown that topical thymosin beta 4 (Tß4) as an adjunct to ciprofloxacin treatment reduces inflammatory mediators and inflammatory cell infiltrates (neutrophils/PMN and macrophages/MΦ) while enhancing bacterial killing and wound healing pathway activation in an experimental model of P. aeruginosa-induced keratitis. This study aimed to mechanistically examine how Tß4 influences MΦ function in particular, leading to reduced inflammation and enhanced host defense following P. aeruginosa-induced infection of the cornea. Flow cytometry was conducted to profile the phenotype of infiltrating MΦ after infection, while generation of reactive nitrogen species and markers of efferocytosis were detected to assess functional activity. In vitro studies were performed utilizing RAW 264.7 cells to verify and extend the in vivo findings. Tß4 treatment decreases MΦ infiltration and regulates the activation state in response to infected corneas. MΦ functional data demonstrated that the adjunctive Tß4 treatment group significantly downregulated reactive nitrogen species (RNS) production and efferocytotic activity. In addition, the in vitro studies showed that both Tß4 alone and adjunctive Tß4 treatment influenced MΦ cellular function following LPS stimulation. Collectively, these data provide further evidence that adjunctive Tß4 + ciprofloxacin treatment offers a more efficacious option for treating bacterial keratitis. Not only does the adjunctive therapy address both the infectious pathogen and corneal wound healing response, but it also influences MΦ infiltration, activation, and function, as revealed by the current study.

Antimicrobial Effects of Thymosin Beta-4 and Ciprofloxacin Adjunctive Therapy in Pseudomonas aeruginosa Induced Keratitis.

Prior work has indicated that thymosin beta 4 (Tß4) administered with ciprofloxacin markedly improves disease outcome for Pseudomonas aeruginosa (PA)-induced keratitis. As a result, the goal of the current study was to elucidate mechanisms by which Tß4 mitigates the corneal response; specifically, regarding its bactericidal influence and potential synergy with ciprofloxacin. An in vitro approach was carried out using minimum inhibitory concentration (MIC) assays to assess bactericidal activity against PA. In addition, antimicrobial peptide (AMP) production was evaluated at the mRNA levels using human corneal epithelial cells in response to lipopolysaccharide (LPS) challenge. The results of the MIC assays did not show direct bactericidal activity with Tß4 alone, although ciprofloxacin exhibited significant killing at concentrations far lower than clinically dosed. Tß4, however, displayed an indirect effect on bacterial killing, as shown by an upregulation of AMPs and related molecules. The cumulative data from this study indicate an indirect bactericidal role of Tß4, as well as a synergistic relationship with ciprofloxacin. Furthermore, ciprofloxacin alone was found to influence cellular functions that otherwise have yet to be reported. These results highlight a mechanism of intracellular communication for Tß4 and further strengthen its development as an adjunct therapy with antibiotics for corneal infections.

Thymosin Beta-4 and Ciprofloxacin Adjunctive Therapy Improves Pseudomonas aeruginosa-Induced Keratitis.

With increasing multidrug resistance and contraindication for corticosteroid use, the goal of this study was to develop thymosin beta-4 (Tß4) as an adjunctive therapy to antibiotics for the treatment of bacterial keratitis that effectively promotes enhanced wound healing, host defense, and inflammation resolution. Disease outcome was assessed by clinical score, slit lamp photography, and histopathology. Cytokine profile, bacterial load, PMN infiltration, and Griess and reactive oxygen species (ROS) levels were determined. Adjunct Tß4 treatment resulted in a significant improvement compared to PBS, Tß4, and most remarkably, ciprofloxacin, correlating with changes in mediators of inflammation and wound healing. Collectively, these data provide evidence that wound healing is an essential aspect in the development of new therapies to treat corneal infection. Use of adjunctive Tß4 provides a more efficacious approach for bacterial keratitis by addressing both the infectious pathogen and deleterious host response.

Thymosin beta 4 and the eye: the journey from bench to bedside.

INTRODUCTION: Thymosin beta 4 (Tß4) has important applications in ocular repair and Phase 3 clinical trials using Tß4 to treat dry eye and neurotrophic keratopathy are currently ongoing. These exciting clinical possibilities for Tß4 in the eye are the result of seminal basic scientific discoveries and contributions from so many talented investigators. Areas covered: My personal Tß4 journey began at the NIH in 1998 and propelled my career as a clinician scientist. As a tribute to the amazing individuals who have guided and supported me along with my brilliant colleagues and students who have contributed and collaborated with me over the years, this review will tell the cumulative story of how Tß4 became a major potential new therapy for corneal wound healing disorders. The journey has been marked by the thrilling exhilaration from fundamental breakthroughs in the laboratory and clinic, combined with the challenging and often harsh realities of submitting grants and obtaining funding. Expert opinion: The electrifying possibility of Tß4 as a revolutionary novel dry eye therapy is something that could have only been dreamed about just a few years ago. We believe that Tß4 eyedrops will help many patients suffering from several ocular surface related disorders.

RGN-259 (thymosin ß4) improves clinically important dry eye efficacies in comparison with prescription drugs in a dry eye model.

This study evaluated the clinical activity of RGN-259 (thymosin ß4) in comparison with cyclosporine A (CsA), diquafosol (DQS), and lifitegrast (LFA) in a murine model of dry eye. The model was NOD.B10-H2b mice in a 30-40% humidified environment together with daily scopolamine hydrobromide injections for 10 days. After desiccation stress, all drugs were evaluated after 10 treatment days. RGN-259 increased tear production similar to that in the DQS- and LFA-treated mice while CsA was inactive. RGN-259 improved corneal smoothness and decreased fluorescein staining similar to that of LFA group while CsA and DQS were inactive. Corneal epithelial detachment was reduced by RGN-259, and DQS and LFA showed similar activity but the CsA was inactive. RGN-259 increased conjunctival goblet cells and mucin production comparable to that seen with CsA, while DQS and LFA were inactive. RGN-259 reduced the over-expression of inflammatory factors comparable to that with CsA and LFA, while DQS was inactive. RGN-259 increased mucin production comparable to that observed with CsA, while DQS and LFA were inactive. In conclusion, RGN-259 promoted recovery of mucins and goblet cells, improved corneal integrity, and reduced inflammation in a dry eye mouse model and was equal to or more effective than prescription treatments.

Ocular dirofilariasis: Ophthalmic implication of climate change on vector-borne parasites.

PURPOSE: To describe a geographically rare case of ophthalmic dirofilariasis. OBSERVATIONS: An 81-year-old male of good socioeconomic status living in the state of Michigan in the United States, presented to the eye clinic with a painful red left eye. He had not traveled outside of the state of Michigan in over three years. He was found to have a 7 cm long subconjunctival roundworm, which was ultimately extracted. CONCLUSIONS AND IMPORTANCE: With increasing global temperatures, ocular dirofilariasis is being introduced in more northern climates and should be included in the differential diagnosis in areas previously isolated from these vector-borne parasites.

Primary Mechanisms of Thymosin ß4 Repair Activity in Dry Eye Disorders and Other Tissue Injuries.

Dry eye disorders are becoming more common due to many causes, including an aging population, increased pollution, and postrefractive surgery. Current treatments include artificial tears; gels; lubricants; tear duct plugs; and anti-inflammatory agents such as steroids, doxycycline, and cyclosporine. For more severe forms of the disease, serum tears and scleral contact lenses are employed. Despite these therapies, successful resolution of the problem is limited because none of these treatments fully addresses the underlying causes of dry eye to promote ocular surface repair. Thymosin ß4 (Tß4), a small, naturally occurring protein, promotes complete and faster corneal healing than saline alone or prescription agents (doxycycline and cyclosporine) in various animal models of eye injury. In human trials, it improves both the signs and symptoms of moderate to severe dry eye with effects lasting beyond the treatment period. This review will cover the multiple activities of Tß4 on cell migration, inflammation, apoptosis, cytoprotection, and gene expression with a focus on mechanisms of cell migration, including laminin-332 synthesis and degradation, that account for this paradigm-shifting potential new treatment for dry eye disorders. We will also speculate on additional mechanisms that might promote eye repair based on data from other tissue injury models. Such studies provide the rationale for use of Tß4 in other types of eye disorders beyond dry eye. Finally, we will identify the gaps in our knowledge and propose future research avenues.

Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE™) model.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of thymosin beta 4 ophthalmic solution (RGN-259; Tß4) in subjects with moderate to severe dry eye using the CAE™ model. METHODS: This single-center, prospective, double-masked, placebo-controlled Phase II study randomized 72 qualifying subjects 1:1 to receive either 0.1% Tß4 or placebo treatment for a total of 28 days. The study consisted of six visits over a 32-day period, including a screening visit (day -1), controlled adverse environment challenge (CAE) visits (day 1, day 28), and follow-up visits (days 14, 29, and 30). The primary efficacy endpoints were ocular discomfort scores and inferior corneal staining measured at visit 5 on day 29. Secondary endpoints included central and superior corneal staining, conjunctival staining, conjunctival redness, tear-film break-up time, and daily symptom scores recorded over the course of the study. Safety measures included visual acuity, slit-lamp evaluation, conjunctival redness, tear film break-up time, intraocular pressure, dilated funduscopy, and corneal sensitivity. RESULTS: Neither of the primary endpoints, ie, ocular discomfort or inferior corneal staining, showed a significant difference between treatment and control groups at visit 5. Despite this, significant differences between treatment groups were observed for a number of secondary endpoints. The discomfort scores in the CAE on day 28 were reduced by 27% in 0.1% Tß4-treated subjects compared with the placebo group (P=0.0244). Subjects in the 0.1% Tß4 treatment group also showed statistically significant improvements in central and superior corneal staining compared with staining scores in the control group (P=0.0075 and P=0.0210). No adverse events were observed. CONCLUSION: This study confirms the efficacy of 0.1% Tß4 as a topical treatment for relief of signs and symptoms of dry eye. Significant improvements in both signs and symptoms of dry eye were observed, and the treatment exhibited a large safety window, with no adverse events reported by any subjects enrolled in the study.

Thymosin ß4 significantly reduces the signs of dryness in a murine controlled adverse environment model of experimental dry eye.

OBJECTIVE: Dry eye syndrome is a common condition that affects up to 20% of the population aged 45 and older. There are no successful treatments to date. The goal of this research was to determine the efficacy of various doses and the optimal frequency of thymosin ß4 (Tß4) treatment in a murine severe dry eye model. RESEARCH DESIGN AND METHODS: The study was performed using a controlled adverse environment chamber (CAE) in combination with scopolamine to induce moderate to severe dry eye in mice. The study included five mice per group and tested six different doses of Tß4 twice per day for 12 days. Tß4 at 0.1% was also administered 2 - 4 times per day for 12 days. Healing was measured by fluorescein staining. MAIN OUTCOME MEASURES: Tß4 significantly reduced the signs of dry eye relative to controls. The treatment effect was more pronounced than the positive controls, doxycycline and Restasis (cyclosporine 0.05%). Active doses of 0.1 and 0.5% were determined, and it was found that the frequency of dosing at 2 times per day was the most effective for healing. CONCLUSIONS: Tß4 has the potential to be an important new effective therapeutic for dry eye.

Thymosin ß4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial.

PURPOSE: Standard therapies for severe dry eye are limited and fail to resolve the problem. The purpose of this study was to evaluate the safety and efficacy of Thymosin ß4 eye drops (RGN-259) as a novel therapy for severe dry eye disease (including that associated with graft vs. host disease). METHODS: A small, multicenter, randomized, double-masked, placebo-controlled 56-day phase 2 clinical trial including a 28-day follow-up at 2 US sites. Nine patients with severe dry eye were treated with either RGN-259 (0.1%) or vehicle control 6 times daily over a period of 28 days. Dry eye sign and symptom assessments, such as ocular discomfort (using the OSDI questionnaire) and corneal fluorescein staining (using the NEI workshop grading system), were evaluated at various time points. RESULTS: Statistically significant differences in both symptom and sign assessments, were seen at various time points throughout the study. Of particular note at day 56, the RGN-259-treated group (12 eyes) had 35.1% reduction of ocular discomfort compared with vehicle control (6 eyes) (P = 0.0141), and 59.1% reduction of total corneal fluorescein staining compared with vehicle control (P = 0.0108). Other improvements seen in the RGN-259-treated patients included tear film breakup time and increased tear volume production. CONCLUSIONS: In this small trial, RGN-259 eye drops were safe and well tolerated and met key efficacy objectives with statistically significant symptom and sign improvements, compared with vehicle control, at various time intervals, including 28-days posttreatment. CLINICAL TRIAL REGISTRATION--URL: http://www.clinicaltrials.gov. Unique identifier: NCT01393132.

Thymosin ß4: a potential novel dry eye therapy.

The purpose of this manuscript is to review the clinical entity of dry eye syndrome (DES) and to provide a scientific basis and rationale for the usage of thymosin beta 4 (Tß4) as a novel therapy for DES. DES is a common disorder affecting an estimated 25-30 million people in the United States alone and is characterized by inflammation of the ocular surface. Consequently, patients can suffer from burning, irritation, severe discomfort, foreign body sensation, and blurry and decreased vision. Recent animal studies of DES demonstrate that Tß4 eye drops significantly reduce corneal fluorescein staining, indicating improved wound healing. Based on previous studies, there is clear support for further clinical investigation and development of Tß4 as a novel, safe, and effective agent to treat dry eye. Herein, we discuss the scientific and clinical rationales that make Tß4 a potential ideal candidate therapeutic for DES.

Thymosin ß4: a multi-functional regenerative peptide. Basic properties and clinical applications.

INTRODUCTION: Thymosin ß(4), a low molecular weight, naturally-occurring peptide plays a vital role in the repair and regeneration of injured cells and tissues. After injury, thymosin ß(4), is released by platelets, macrophages and many other cell types to protect cells and tissues from further damage and reduce apoptosis, inflammation and microbial growth. Thymosin ß(4) binds to actin and promotes cell migration, including the mobilization, migration, and differentiation of stem/progenitor cells, which form new blood vessels and regenerate the tissue. Thymosin ß(4) also decreases the number of myofibroblasts in wounds, resulting in decreased scar formation and fibrosis. AREAS COVERED: This article will cover the many thymosin ß(4) activities that directly affect the repair and regeneration cascade with emphasis on its therapeutic uses and potential. Our approach has been to evaluate the basic biology of the molecule as well as its potential for clinical applications in the skin, eye, heart and brain. EXPERT OPINION: The considerable advances in our understanding of the functional biology and mechanisms of action of thymosin ß(4) have provided the scientific foundation for ongoing and projected clinical trials in the treatment of dermal wounds, corneal injuries and in the regeneration and repair of heart and CNS tissue following ischemic insults and trauma.

Thymosin beta4 inhibits TNF-alpha-induced NF-kappaB activation, IL-8 expression, and the sensitizing effects by its partners PINCH-1 and ILK.

The mechanisms by which thymosin ß 4 (Tß(4)) regulates the inflammatory response to injury are poorly understood. Previously, we demonstrated that ectopic Tß(4) treatment inhibits injury-induced proinflammatory cytokine and chemokine production. We have also shown that Tß(4) suppresses TNF-α-mediated NF-κB activation. Herein, we present novel evidence that Tß(4) directly targets the NF-κB RelA/p65 subunit. We find that enforced expression of Tß(4) interferes with TNF-α-mediated NF-κB activation, as well as downstream IL-8 gene transcription. These activities are independent of the G-actin-binding properties of Tß(4). Tß(4) blocks RelA/p65 nuclear translocation and targeting to the cognate κB site in the proximal region of the IL-8 gene promoter. Tß(4) also inhibits the sensitizing effects of its intracellular binding partners, PINCH-1 and ILK, on NF-κB activity after TNF-α stimulation. The identification of a functional regulatory role by Tß(4) and the focal adhesion proteins PINCH-1 and ILK on NF-κB activity in this study opens a new window for scientific exploration of how Tß(4) modulates inflammation. In addition, the results of this study serve as a foundation for developing Tß(4) as a new anti-inflammatory therapy.

Whole blood, flow-chamber studies in real-time indicate a biphasic role for thymosin ß-4 in platelet adhesion.

BACKGROUND: Thymosin beta 4 (Tß(4)) is a major actin sequestering peptide present in most mammalian cells. It also acts as an anti-inflammatory agent and promotes corneal wound healing. METHODS: In the present study, we constructed a four channel cylindrical flow chambers out of polydimethylsiloxane (PDMS) on microscope coverslips. The platelet-binding proteins-fibrinogen and collagen-were immobilized onto the middle ~25% of the inner cylindrical surface. The flow method introduced here was employed to determine the effect of Tß(4), on the deposition of ADP-activated platelets onto fibrinogen cross-linked flow chambers. RESULTS: The binding data from the flow chambers indicated that the both the rate constant of platelet deposition (average: 0.026±0.0015s(-1), corresponding to a half-life of 26.7s) and the total number of deposited platelets were independent of the platelet binding protein and the activating agent. Our results show that low concentrations of Tß(4) (0.2 µM to 0.5 µM) increased both the rate constant of platelet deposition by ~1.5-fold (i.e. half-life decreased from 26.7s to 17.6s) and the total number of deposited platelets by ~3-fold. However at higher concentrations (>1 µM) the Tß(4)-potentiating effect was diminished to near control levels. Tß(4) did interact with fibrinogen with an estimated K(D) of ~126±18nM or 66±20nM under equilibrium or flow, respectively. CONCLUSION: These results suggest that Tß(4) could potentially increase the affinity of platelet receptors for their ligands thus promoting platelet deposition. Tß(4) could also bind to fibrinogen and as its concentration increased would prevent platelet-fibrinogen interactions resulting in the attenuation of platelet deposition. GENERAL SIGNIFICANCE: This work suggests that Tß(4) might have a dual role in platelet function.

Thymosin beta4 and corneal wound healing: visions of the future.

Persistent corneal epithelial defects and inflammation within the central cornea can directly distort visual acuity and may lead to permanent visual loss. Therefore, treatments with agents that enhance corneal reepithelialization and regulate the inflammatory response without the deleterious side effects of currently used agents such as corticosteroids would result in improved clinical outcome and would represent a major advance in the field. Despite much progress in the areas of corneal wound healing research, clinically available pharmacological therapies that can promote repair and limit the visual complications from persistent corneal wounds are severely limited and remains a major deficiency in the field. Prior studies from our laboratory have demonstrated the potent wound healing and anti-inflammatory effects of thymosin beta4 (Tbeta(4); Tbeta4) in numerous models of corneal injury. We are studying the mechanisms by which Tbeta(4) suppresses inflammation and promotes repair. Herein, we discuss some of our new basic scientific directions that may lead to the use of Tbeta(4) as a novel corneal wound healing and anti-inflammatory therapy.

Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4.

Neurotrophic corneal defects are difficult to heal and all too often lead to scarring and vision loss. Medical management is often of limited success. We describe the results of nine patients (ages 37-84) with chronic nonhealing neurotrophic corneal epithelial defects who were treated with thymosin beta 4 (Tbeta4) sterile eye drops for 28 or 49 days with a follow-up period of 30 days. Those with geographic defects (six patients) showed dramatic healing without clinically significant neovascularization. Stromal thinning was observed in one patient. Three patients with punctate epithelial defects did not have a demonstrable change in their clinical findings. Reduced ocular irritation was reported by all patients soon after treatment initiation. Results from these compassionate use cases indicate that Tbeta4 may provide a novel, topical approach to wound healing in chronic nonhealing neurotrophic corneal ulcers.