Therapy For Retinopathy Of Prematurity Research Articles

Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity

Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Complications of ROP treated at investigator discretion (no study treatment). Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. ClinicalTrials.gov Identifier: NCT04015180.

Delayed anterior segment complications after the treatment of retinopathy of prematurity with laser photocoagulation

PurposeThis retrospective cohort study presents a group of patients who underwent laser therapy for retinopathy of prematurity and presented with delayed anterior segment complications.MethodsThe charts of infants treated with laser photocoagulation for retinopathy of prematurity at our institution between 1988 and 2020 were reviewed. The data extracted included demographics, treatment and clinical examination findings, and those on visual acuity, surgical procedures, and cycloplegic refraction. The inclusion criteria were documented anterior segment changes during the follow-up period. The exclusion criteria were any prior intraocular surgery or inflammation before signs of anterior segment complications developed. The exposure was laser photocoagulation for retinopathy of prematurity and the main outcomes were anterior segment complications, visual acuity, and cycloplegic refraction.ResultsA total of 183 charts were reviewed. Sixteen eyes of nine patients (4.4%) met the inclusion criteria. The mean follow-up period after laser treatment was 15.9 years (range 10 years–26 years). The mean gestational age at birth was 24.6 weeks (range 23 weeks–27 weeks), and the mean age at first clinical documentation of anterior segment complications was 8.7 years (range 1 years–25 years). The complications included cataract (n = five patients/eight eyes) and glaucoma (n = three patients/five eyes), with the most frequent complication being band keratopathy (n = nine patients/15 eyes). A total of five out of 16 eyes underwent surgical procedures due to anterior segment complications. After treatment, visual acuity improved back to its baseline value in four out of five of the treated eyes, and improved, but not to its baseline value, in one out of five of the treated eyes. All the patients developed progressive high myopia over the follow-up period.ConclusionsAnterior segment complications after laser photocoagulation for retinopathy of prematurity may develop later in life. They affect patients’ visual acuity and quality of life and may require treatment.

Nailfold Capillaroscopy: A Promising, Noninvasive Approach to Predict Retinopathy of Prematurity

To test the hypothesis that nailfold capillaroscopy can noninvasively detect dysregulated retinal angiogenesis and predict retinopathy of prematurity (ROP) in infants born premature before its development. In a cohort of 32 infants born <33weeks of gestation, 1386 nailfold capillary network images of the 3 middle fingers of each hand were taken during the first month of life. From these, 25 infants had paired data taken 2 weeks apart during the first month of life. Images were analyzed for metrics of peripheral microvascular density using a machine learning-based segmentation approach and a previously validated microvascular quantification platform (REAVER vascular analysis). Results were correlated with subsequent development of ROP based on a published consensus ROP severity scale. In total, 18 of 32 (56%) (entire cohort) and 13 of 25 (52%) (2-time point subgroup) developed ROP. Peripheral vascular density decreased significantly during the first month of life. In the paired time point analysis, vessel length density, a key metric of peripheral vascular density, was significantly greater at both time points among infants who later developed ROP (15 563 and 11 996μm/mm2, respectively) compared with infants who did not (12 252 and 8845μm/mm2, respectively) (P<.001, both time points). A vessel length density cutoff of >15 100 at T1 or at T2 correctly detected 3 of 3 infants requiring ROP therapy. In a mixed-effects linear regression model, peripheral vascular density metrics were significantly correlated with ROP severity. Nailfold microvascular density assessed during the first month of life is a promising, noninvasive biomarker to identify premature infants at highest risk for ROP before detection on eye exam.

A Multicenter Cross-Sectional Study of the Awareness and Screening for Retinopathy of Prematurity Among NICU Pediatricians in Makkah and Jeddah, Saudi Arabia.

Purpose This study aims to evaluate neonatal intensive care unit (NICU) pediatricians' knowledge about retinopathy of prematurity (ROP) in the major tertiary centers in Makkah and Jeddah, Saudi Arabia. Methods This cross-sectional study uses a self-administered electronic questionnaire completed by NICU pediatricians at the main hospitals of Makkah and Jeddah cities. Based on the participants' correctly selected responses to the validated questionnaire, a scoring system was used in the data analysis to show their level of ROP knowledge. Results Seventy-seven responses were analyzed. The male gender was 49.4%. The majority were recruited from the ministry of health hospitals (63.6%). A small proportion (28.6%) correctly identified who performs the examination. Around three-quarters of the participants have correctly stated that ROP therapy is a very good option to prevent blindness (72.7%). The treatment should generally begin within 72 hours after diagnosis of sight-threatening ROP (79.2%). The requirements for ROP screening were unknown to more than half of our participants (53.2%). With the lowest score of 4.0 and a maximum score of 17.0, the median knowledge score was 13.0 (IQR = 11.0 to 14.0). Based on pediatricians' clinical qualifications, knowledge scores varied significantly. Residents had a significantly lower knowledge score than specialists and consultants (median = 7.0, IQR = 6.0 to 9.0, p = 0.001). Additionally, pediatricians with less experience (<5 years) performed significantly lower on the knowledge score (median = 10.0, IQR = 6.2 to 12.8) than those with more experience (median = 13.0, IQR = 11.0 to 15.0) for participants with 5-10 years of experience, and (median = 13.0, IQR = 11.0 to 14.0) for participants with >10 years of experience). Conclusion Our study showed that NICU pediatricians understood ROP risk factors and treatment options. Nevertheless, they needed to understand the ROP screening inclusion criteria and when the screening could be stopped. Residents scored substantially lower in knowledge overall. Accordingly, we emphasized the need for NICU pediatricians to increase their level of awareness by having regular educational sessions and standardizing one guideline to be strictly followed.

Ferrostatin-1 attenuates pathological angiogenesis in oxygen-induced retinopathy via inhibition of ferroptosis

Retinopathy of prematurity (ROP) is a vision-threatening ocular disease that occurs in premature infants, but the underlying mechanism is still unclear. Since oxidative stress has been well documented in the ROP development, we aimed to investigate whether ferroptosis, a new type of cell death characterized by lipid peroxidation and iron overload, is also involved in ROP. We detected the lipid peroxidation, oxidative stress and the expression of ferroptosis markers in the retina of mouse model of oxygen-induced retinopathy. After ferroptosis inhibitor, ferrostatin-1, was administered by intravitreal injection, ferroptosis marker, lipid peroxidation, retinal vasculature and glial cell activation were examined. We found decreased expression of SLC7A11 and GPX4, increased expression of FTH1 and TFRC, as well as increase of lipid peroxidation in the retina of OIR mice. Ferrostatin-1 administration significantly reduced lipid peroxidation, and also reversed the change of ferroptosis marker. Neovascular area and avascular area were suppressed and the pathological vasculature changes including acellular vessels and ghost pericytes were decreased. Microglial cell and Müller cell activation was not evidently influenced by ferrostatin-1 treatment. Our findings suggest that ferroptosis is involved in the pathological angiogenesis and might be a promising target for ROP therapy.

Midazolam Induced Abnormal Movements in Preterm Newborns: Case Series

Objectives − The aim of our article is to highlight the adverse effects of midazolam, which causes abnormal behavior and a paradoxical behavioral reaction, although it is used for sedation and seizure control, as well as preoperative and procedure-related sedation in neonates.Case Presentation − We report myoclonic seizure-like abnormal activity in four preterm neonates, who received intravenous midazolam for sedation before laser photocoagulation for retinopathy of prematurity and seizures. All neonates had a long NICU stay, but were clinically well before undergoing the procedure. Cases 1, 2 and 3 developed multifocal seizure-like abnormal movements after receiving a midazolam injection for photocoagulation therapy for retinopathy of prematurity. Case 4 developed multifocal seizure-like abnormal movements after receiving an injection of midazolam for seizures. In all the cases the seizure-like abnormal movements were controlled by phenobarbitone.Conclusion − Midazolam is increasingly being used in NICUs, but caution must be exercised while administering it in preterm neonates with comorbidities. It is difficult to identify the neonates at risk, but it is necessary to be aware of and cautious about the adverse effects of midazolam when administering the drug.

Pulmonary Hypertension in Preterm Infants Treated With Laser vs Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity

Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified. To determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment. This multicenter retrospective cohort study took place at neonatal intensive care units of 48 children's hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation. Anti-VEGF therapy vs laser photocoagulation. New receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening. Among 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks' postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10). Anti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

Pulmonary Hypertension and Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity—Is There a Link?

Pulmonary Hypertension and Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity—Is There a Link?

Immunomodulation of MiRNA-223-based nanoplatform for targeted therapy in retinopathy of prematurity.

Retinopathy of prematurity (ROP) is characterized by pathological angiogenesis and associated inflammation in the retina and is the leading cause of childhood blindness. MiRNA-223 (miR-223) drives microglial polarization toward the anti-inflammatory phenotype and offers a therapeutic approach to suppress inflammation and consequently pathological neovascularization. However, miRNA-based therapy is hindered by the low stability and non-specific cell-targeting ability of delivery systems. In the present study, we developed folic acid-chitosan (FA-CS)-modified mesoporous silica nanoparticles (PMSN) loaded with miR-223 to regulate retinal microglial polarization. The FA-CS/PMSN/miR-223 nanoparticles exhibited high stability and loading efficiency, achieved targeted delivery, and successfully escaped from lysosomes. In cultured microglial cells, treatment with FA-CS/PMSN/miR-223 nanoparticles upregulated the anti-inflammatory gene YM1/2 and IL-4RA, and downregulated the proinflammatory genes iNOS, IL-1β, and IL-6. Notably, in a mouse oxygen-induced retinopathy model of ROP, intravitreally injected FA-CS/PMSN/miR-223 nanoparticles (1μg) decreased the retinal neovascular area by 52.6%. This protective effect was associated with the reduced and increased levels of pro-inflammatory (M1) and anti-inflammatory (M2) cytokines, respectively. Collectively, these findings demonstrate that FA-CS/PMSN/miR-223 nanoparticles provide an effective therapeutic strategy for the treatment of ROP by modulating the miR-223-mediated microglial polarization to the M2 phenotype.

Development of myopia in laser-treated ROP infants: prematurity or laser photocoagulation?

To investigate the relationship between the development of corrected 1-year-old refraction values and risk factors in preterm infants who underwent laser photocoagulation (LPC) therapy for retinopathy of prematurity (ROP). The ophthalmic examination findings of preterm neonates who had developed Type I ROP and received LPC therapy were evaluated retrospectively. The association between spherical equivalent (SE) values and clinical findings were analyzed by using multivariable linear regression analysis. The study included 157 eyes of 80 neonates with a mean birth week of 27.1 ± 2.2weeks (23 to 32weeks) and a mean birth weight of 995 ± 273g (565 to 1760g). The treatments were administered on an average of 36.8 ± 2.7 (32 to 45weeks) postmenstrual age. LPC treatment was applied bilaterally to 77 of the 80 neonates included in the study, and unilaterally to 3 of them. The mean ± standard deviation of the SE value was 0.31 ± 1.89 diopters (D) (-8.00 to 4.63 D) according to the results of the 1-year corrected age refraction examination. In univariate analysis, no significant association between GA, BW, and ROP zone and SE value, while the number of laser spots (ß = - 0.27 ± 0.00 D, p = 0.00) and stage 3 ROP (ß = - 0.29 ± 0.37 D, p = 0.00) were significantly associated with the SE value. In multivariable linear regression analysis, a significant association between number of laser spot, stage 3 ROP and SE value (ß = - 0.25 ± 0.00 D, p = 0.01 for number of laser spot, ß = - 0.28 ± 0.36 D, p = 0.00 for stage 3 ROP). In conclusion, this study supports that stage of ROP and the number of laser spots count applied in photocoagulation treatment for ROP is significantly correlated with degree of myopia (p < 0.05).

A single intravenous injection of cyclosporin A-loaded lipid nanocapsules prevents retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy. To overcome these limitations, we developed a nanotherapeutic that effectively prevents ROP development with one simple intravenous injection. Its lipid nanocapsules transport the antiangiogenic and anti-inflammatory cyclosporin A efficiently into disease-driving retinal pigment epithelium cells. In a mouse model of ROP, a single intravenous injection of the nanotherapeutic prevented ROP and led to normal retinal development by counteracting neovascularization and inflammation. This nanotherapeutic approach has the potential to bring about a change of paradigm in ROP therapy and prevent millions of preterm born infants from developing ROP.

Exploration of Hub Genes in Retinopathy of Prematurity Based on Bioinformatics Analysis of the Oxygen-Induced Retinopathy Model.

Retinopathy of prematurity (ROP) is a major blindness-causing disease that is characterized by an arrest of normal vascular development and neovascularization of the retina. Previous studies have shown that genetic factors may be associated with the development and severity of ROP. However, the genes and mechanisms underlying ROP remain unclear. We aimed to identify hub genes in ROP and drugs related to these genes by integrative analysis. The expression profiles of GSE158799 and GSE135844 were acquired from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified. Then, an integrative analysis was performed including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), protein-protein interaction (PPI) network, transcription factor (TF)-gene, and miRNA-gene networks analysis. Moreover, we verified hub genes and identified potential drugs. 225 common DEGs were identified. Biological function analysis indicated that angiogenesis, cell surface, cell adhesion, extracellular matrix, and focal adhesion genes were enriched among DEGs. The PI3K/Akt signalingpathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction were markedly enriched in the KEGG pathway analysis. Finally, 5 hub genes related to the nosogenesis of ROP were identified and found to be targeted by VEGFA inhibitors, TLR4 antagonists, and sunitinib. The present study showed that VEGFA, ACTA2, MKI67, CD68, and TLR4 are potential hub genes involved in the pathogenesis of ROP. Moreover, TLR4 antagonists and sunitinib may be new candidate drugs for ROP therapy, in addition to VEGFA inhibitors.

Comparison of Intravitreal Anti-VEGF Agents With Laser Photocoagulation for Retinopathy of Prematurity of 1,627 Eyes in China.

PurposeTo compare the efficacies and treatment outcomes of intravitreal anti-VEGF agents and laser therapy in retinopathy of prematurity (ROP).MethodsA retrospective, non-randomized, comparative study of patients diagnosed with type 1 ROP or aggressive posterior ROP (A-ROP) treated with intravitreal anti-VEGF agents or laser therapy as primary treatment at the People's Hospital of Peking University.ResultsA total of 1,627 eyes of 862 patients were included. In Group 1, 399 eyes of 204 patients were diagnosed with A-ROP or zone I type 1 ROP. The initial regression of the anti-VEGF subgroup was better than that of the laser subgroup, and the reactivation rate and rate of progression to retinal detachment were lower than those of the laser subgroup. In Group 2, 1,228 eyes of 658 patients were diagnosed with zone II type 1 ROP. The reactivation rate of the laser subgroup was lower than that of the anti-VEGF subgroup. No significant differences were found in the initial regression and the probability of developing retinal detachment. Among the anti-VEGF agents, the reactivation rate in eyes treated with conbercept was much lower than that in eyes treated with ranibizumab. The spherical power and spherical equivalents of eyes treated with laser were significantly higher than those of eyes treated with anti-VEGF agents 1 year after initial treatment.ConclusionsIn contrast to laser therapy, anti-VEGF agents as primary treatments have potential advantages for eyes with zone I type 1 ROP and A-ROP. For eyes with zone II type 1 ROP, laser photocoagulation and anti-VEGF agents therapy showed similar efficacy; however, the rate of reactivation with laser therapy was significantly lower than that with anti-VEGF agents. Among the anti-VEGF agents, the reactivation rate was much lower in eyes treated with conbercept than in eyes treated with ranibizumab. Compared to anti-VEGF agents, laser treated eyes had greater trend to myopia.

Major cardiorespiratory events do not increase after immunizations, eye exams, and other stressors in most very low birth weight infants.

Increased cardiorespiratory events with bradycardia and oxygen desaturation have been reported in very low birthweight (VLBW) infants following stressors such as immunizations. These events are difficult to quantify and may be mild. Our group developed an automated algorithm to analyze bedside monitor data from NICU patients for events with bradycardia and prolonged oxygen desaturation (BDs) and used this to compare BDs 24 hours before and after potentially stressful interventions. We included VLBW infants from 2012-2017 with data available around at least one of four interventions: two-month immunizations, retinopathy of prematurity (ROP) examinations, ROP therapy, and inguinal hernia surgery. We used a validated algorithm to analyze electrocardiogram heart rate and pulse oximeter saturation data (HR, SpO2) to quantify BD events of HR < 100 beats/minute for≥4 seconds with oxygen desaturation < 80%SpO2 for≥10 seconds. BDs were analyzed 24 hours before and after interventions using Wilcoxon rank-sum tests. In 354 of 493 (72%) interventions, BD frequency stayed the same or decreased in the 24 hours after the event. An increase of at least five BD's occurred in 17/146 (12%) after immunizations, 85/290 (29%) after ROP examinations, 4/33 (12%) after ROP therapy, and 3/25 (12%) after hernia surgery. Infants with an increase in BDs after interventions had similar demographics compared to those without. More infants with an increase in BDs following immunizations were on CPAP or caffeine than those without. Most VLBW infants in our cohort had no increase in significant cardiorespiratory events in the 24 hours following potentially stressful interventions.

Characteristics of Eyes Developing Retinal Detachment After Anti-vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity.

BackgroundWe investigated the incidence and clinical characteristics of eyes showing retinal detachment (RD) after anti-vascular endothelial growth factor (VEGF) for retinopathy of prematurity (ROP).MethodsA retrospective chart review of 76 consecutive eyes of 45 patients (18 girls and 27 boys) with stage 3 ROP who received anti-VEGF therapy between January 2012 and August 2020 with a minimum follow-up of 6 months was conducted. Eyes were divided into two groups: the vitrectomy (V) group that required vitrectomy for RD after anti-VEGF therapy and the non-vitrectomy (non-V) group that did not require vitrectomy. Data were collected from patient charts, including sex, postmenstrual age (PMA) at birth, birth weight, PMA at anti-VEGF therapy, comorbidities, reactivation, examination interval, and subsequent vitrectomies.ResultsThe median PMA at birth was 24.7 (range, 22.1–29.3) weeks. Twenty-seven eyes (35.1%) exhibited ROP reactivation at 6.4 ± 3.1 weeks after anti-VEGF therapy. The V group included six eyes of five patients, all of whom exhibited reactivation and developed RD 10.1 ± 6.5 weeks after anti-VEGF therapy. The types of RD were conventional (classic) in two eyes and circumferential (unique to RD after anti-VEGF) in four eyes. Three eyes required repeated vitrectomy. All eyes, except one eye in the V group, achieved retinal attachment at the last examination. The non-V group included 70 eyes of 40 patients, of which 21 exhibited reactivation and were treated successfully with laser (17 eyes) or second anti-VEGF (4 eyes). The proportion of eyes with plus disease was significantly higher in the V group (50.0%) than in the non-V group (10.0%) (P = 0.035). V group included 3 of 22 eyes (13.6%) in which the interval between the last examination and the diagnosis of reactivation was <1 week and 3 of 5 eyes (60.0%) in which the interval was more than 1 week (P = 0.024). The two groups showed no significant differences in the other factors.ConclusionApproximately 8% of eyes developed RD about 10 weeks after anti-VEGF therapy for ROP. Eyes with history of plus disease should be carefully monitored at appropriate intervals after anti-VEGF therapy for ROP.

Progression of retinal vascularization after intravitreal anti-vascular-endothelial growth factor therapy in retinopathy of prematurity

BackgroundAnti-vascular endothelial growth factor (Anti-VEGF) therapy is now considered as one of standard therapies in approaching infants with retinopathy of prematurity (ROP). The purpose of this study was to assess the time to full retinal vascularization in infants with ROP who were treated with intravitreal bevacizumab (IVB).MethodsThis retrospective cohort study evaluated premature infants with ROP who were treated with IVB between 2012 and 2019. Demographic and clinical data were collected from the medical records and analyzed. Main outcomes were defined as time to complete vascularization and time of zone shift.ResultsEight hundred sixty-five eyes from 441 patients were included. Average gestational age and birth weight were 28 ± 4 weeks and 1121 ± 624 g, respectively. Primary treatment failure and reactivation occurred in 35 eyes (4.0%) and 33 eyes (3.8%), respectively. Recurrent ROP occurred significantly more frequently in infants with pre-treatment zone 1 ROP compared to those with zone 2 ROP (7.6% versus 3%, p < 0.01). Patients with pre-treatment zone 2 reached zone 3 faster than those with pre-treatment zone 1 (142 ± 152 days versus 181 ± 174 days, p < 0.01); however, the time until full retinal vascularization did not significantly differ between the groups (p = 0.10).ConclusionThis study revealed that pre-treatment ROP zone was associated with ROP reactivation rate but not with time to full vascularization in those treated with IVB.Trial registration Retrospectively registered; IR.TUMS.FARABI.REC.1399.040

Comparative Analysis of Intravitreal Ranibizumab versus Laser Therapy for Retinopathy of Prematurity

Comparative Analysis of Intravitreal Ranibizumab versus Laser Therapy for Retinopathy of Prematurity

Anti-vascular endothelial growth factor therapy in retinopathy of prematurity: An updated literature review.

Laser photocoagulation can still be considered the gold standard for treatment for retinopathy of prematurity (ROP). However, anti-vascular endothelial growth factor (anti-VEGF) therapy has increasingly become an important option that plays a significant role in the treatment of ROP. Major clinical trials have been published regarding the anti-VEGF use in ROP, along with multiple other studies looking into the different agents, doses, techniques, and possible complications. Anti-VEGF therapies can be considered as a safe and effective option for managing ROP. More longitudinal randomized clinical trials are necessary to evaluate the preferred treatment agent, the appropriate dose, best follow-up protocol, and the long-term ocular and systemic outcomes following treatment.

Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.

Optimal Efficacy and Safety of Humanized Anti-Scg3 Antibody to Alleviate Oxygen-Induced Retinopathy.

The retinopathy of prematurity (ROP), a neovascular retinal disorder presenting in premature infants, is the leading causes of blindness in children. Currently, there is no approved drug therapy for ROP in the U.S., highlighting the urgent unmet clinical need for a novel therapeutic to treat the disease. Secretogranin III (Scg3) was recently identified as a disease-selective angiogenic factor, and Scg3-neutralizing monoclonal antibodies were reported to alleviate pathological retinal neovascularization in mouse models. In this study, we characterized the efficacy and safety of a full-length humanized anti-Scg3 antibody (hAb) to ameliorate retinal pathology in oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, by implementing histological and functional analyses. Our results demonstrate that the anti-Scg3 hAb outperforms the vascular endothelial growth factor inhibitor aflibercept in terms of efficacy and safety to treat OIR mice. Our findings support the development of anti-Scg3 hAb for clinical application.