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ABSTRACT Purpose: To evaluate the retinal vascularization process after intravitreal ranibizumab was administered to infants with aggressive posterior retinopathy of prematurity (AP-ROP). Methods: Twenty-six eyes of 13 infants with AP-ROP who received 0.25 mg intravitreal ranibizumab were retrospectively investigated. The patients were evaluated at weekly follow-up visits, and the findings were analyzed after retinal vascularization was complete. Results: The results showed regression in the AP-ROP of all the patients within the first 48-72 h. Average time for complete vascularization of the nasal quadrant (zone II) was postmenstrual week 45 (range 41-56), and vascularization of the temporal quadrant (zone III) was completed in the postmenstrual week 56 (range 50-65). Reactivation was observed in seven patients, on average at postmenstrual week 42; two of these patients underwent additional treatment. Two patients presented with avascular areas in the peripheral retina despite being 1 year old. Conclusion: These results showed that retinal vascularization following intravitreal ranibizumab was completed after a delay in patients with AP-ROP. Further studies are necessary to evaluate when and how vascularization occurs after intravitreal anti-vascular endothelial growth factor treatments.
RESUMO Objetivo: Avaliar o processo de vascularização da retina após injeção intravítrea de ranibizumab aplicada em crianças com retinopatia da prematuridade posterior agressiva (AP-ROP). Métodos: Vinte e seis olhos de 13 crianças com AP-ROP que receberam 0,25 mg de ranibizumab intravítreo foram investigados retrospectivamente. Os resultados foram avaliados após a completa vascularização da retina, observada em acompanhamentos semanais. Resultados: Verificou-se que houve regressão na AP-ROP de todos os pacientes durante as primeiras 48 a 72 horas. Na média, a vascularização do quadrante nasal (zona II) foi concluída na semana 45 pós-menstrual (variação 41-56), enquanto a vascularização do quadrante temporal (zona III) foi concluída na semana 56 pós-menstrual (variação 50-65). Sete pacientes (7/13) apresentaram reativação, que aconteceram em média a 42,14 semanas pós-menstruais, dois pacientes receberam tratamento adicional. Dois pacientes apresentaram áreas avasculares na retina periférica apesar de terem um ano de idade. Conclusões: O presente estudo mostrou que a vascularização da retina após a injeção intravítrea de ranibizumab foi concluída com atraso na AP-ROP. Ensaios clínicos randomizados são necessários para avaliar quando e como a vascularização acontece após tratamentos com injeções intravítreas de anti-VEGF.
Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Retinopathy of Prematurity/drug therapy , Retinal Neovascularization/drug therapy , Ranibizumab/therapeutic use , Recurrence , Infant, Premature , Retrospective Studies , Follow-Up Studies , Gestational Age , Angiogenesis Inhibitors/therapeutic use , Intravitreal InjectionsABSTRACT
Since anti vascular endothelial growth factor (VEGF) therapy has recently become the first-line treatment of wet age related macular degeneration in China,as well as retinopathy of prematurity,neovascular glaucoma and macular edema secondary to diabetic retinopathy or retinal vein occlusion in other countries,It is worth thinking about that how to perform anti-VEGF treatment properly to benefit more patients.We reviewed the fields of clinical researches to explore the best role of anti-VEGF treatment in prevention and treatment of retinal disease in future.
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Objective To evaluate the inhibitory effect of small interfering RNA (siRNA) targeting peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) on retinal neovascularization in the mouse.Methods Eighty seven-day-old C57BL/6J mice were divided into normal group,model blank group,model control group and PGC-1α siRNA group,twenty mice in each group.Mice in the normal group were kept in normal room air.Mice in the model blank group,model control group and PGC-1α siRNA group were induced for retinal neovascularization by hypoxia.Liposome with PGC-1α siRNA (1 μl) and liposome with negative control siRNA (1 μl) were injected into the vitreous in the PGC-1α siRNA group and model control group respectively when mice were moved out to room air from the cabin (Postnatal 12).No injection were performed in the model blank group.At postnatal 17,fluorescein angiography was used to assess the vascular pattern.The proliferative neovascular response was quantified by counting the nuclei of new vessels extending from the retina into the vitreous in cross-sections.PGC-1α and vascular endothelial growth factor (VEGF) level in retina were measured by real-time polymerase chain reaction (real-time PCR) and Western blot.Inhibition efficiency of PGC-1α siRNA on PGC-1α and VEGF was calculated.Results Mice in the normal group showed reticular distribution of retinal blood vessels.Central nonperfused retina,neovascular tufts and fluorescein leakage were seen in the model blank group and model control group.Neovascular tuft and fluorescein leakage were decreased in the PGC-1α siRNA group compared to the model blank group and model control group.The neovascular nuclei were increased in the model blank group and model control group compared to the normal group (P＜0.05).The neovascular nuclei were decreased in the PGC-1α siRNA group compared to the model blank group and model control group (P＜0.05).The expression of PGC-1α mRNA and protein in retina was increased significantly in the model blank group and model control group as compared with normal group,while decreased 54％ and 53％ respectively in the PGC-1α siRNA group as compared with model blank group and model control group (P＜0.05).The expression of VEGF mRNA and protein in retina was increased significantly in the model blank group and model control group as compared with normal group,while decreased significantly in the PGC-1α siRNA group (decreased 48 ％ and 40 ％ respectively) as compared with model blank group and model control group (P＜0.05).Conclusions Intravitreal injection of PGC-1α siRNA mediated by liposome can inhibit retinal neovascularization in the mouse effectively.
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Objective To explore the inhibition effect of Cysteine-rich 61 (CCN1; Cyr61) specific siRNA expression vector on RNV in a mouse model of oxygen-induced retinopathy (OIR).Methods One hundred and twenty healthy C57BL/6J mice were chosen and randomly divided into the experimental group and control group,with 60 mice in each group.The experimental group was intravitreously injected with CCN1siRNA recombinant plasmids.The control group was injected with vector plasmids.Adenosine diphosphate-ase stained retina flat-mounts was performed to assess the retinal vascular profiles,retinal section with HE staining was applied to count the number of new vascular cell nuclei and the protein and mRNA expression of CCN1 and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry,Western blot and Real-time RT-PCR.Results Compared with control group,regular distributions,good branches and reduced density of retinal neovascularization were observed in the experimental group.The number of nucleus of vascular endothelial cells breaking through the inner limiting membrane was obviously less in the experimental group than that in the control group (t=8.756,P＜ 0.05).The expression of CCN1 and VEGF were obviously decreased in the experimental group compared with the control group (all P＜0.05).Conclusion The development of RNV of ROP can be markedly inhibited by RNA interference targeting CCN1,and CCNlsiRNA may provide an effective method for preventing vascular proliferative retinopathy.
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Objective To observe the inhibitory effect of intravitreal injection of triamcinolone acetonide (TA) on oxygen-induced retinal neovascularization,and to investigate its mechanism.Methods A total of 48 C57BL/6 mice at the age of 7 days were divided into normal group (group A,n=6),high-oxygen group (group B,n=6),TA control group (group C,n=18) and TA high-oxygen group (group D,n=18).The retinal neovascularization of group B and D were induced by oxygen.One eye of each mouse of group C and D received an intravitreal injection 2 μl (20 μg/μl) of TA,and the same volume of BSS was injected into the other eye of the mice as BSS control group (group E) and BSS high-oxygen group (group F).At postnatal day 17,the retinas were collected and the number of the endothelium cell nuclei of new vessels beyond the inner limiting membrane (ILM) was counted on HE-stained paraffin retina sections.The expression level of vascular endothelial growth factor (VEGF),stromal cell-derived factor 1 (SDF-1) and CD14 were measured by immunohistochemical staining.The mRNA expression of VEGF and SDF-1 were detected by real-time RT-PCR.Results The numbers of the endothelium cell nuclei of new vessels beyond the ILM in group A - F were 0,675,0,0,110 and 688 respectively.In group A and D,it decreased than that in group B and F respectively (t=30.62,19.532; P＜0.05).There was no difference of VEGF,SDF-1 and CD14 expression between group C and E (t=0.161,0.284,0.223 ; P＞0.05),but the differences were statistically significant between group D and F(t=-2.264,-2.358,-4.897;P＜0.05).There was no difference on mRNA level of VEGF and SDF-1 between group C and E(t =- 0.497,- 0.709 ; P＜0.05),but the differences were statistically significant between group D and F(z=-5.137,-4.411;P＜0.05).Conclusion Intravitreal injection with TA can inhibit oxygen-induced retinal neovascularization,downregulated expression of VEGF and SDF-1 may be the mechanism.
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Anti-vascular dndothelial growth factor (VEGF) drugs have open up a new treatment channel for ocular neovascular diseases.A lots of clinical data has proved that anti VEGF drugs are effective and safe.But we should also notice that long-term and excessive usage of anti-VEGF drugs brings some new problems and complications,and even affect the normal ocular physiological process of the angiogenesis and retinal blood flow.So,it is necessary to pay attention to the problems and potential risks of excessive usage of anti VEGF therapies for ocular neovascular disease.