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SummaryTransplantation of the retinal pigment epithelium (RPE) is being developed as a cell-replacement therapy for age-related macular degeneration. Human embryonic stem cell (hESC) and induced pluripotent stem cell (iPSC)-derived RPE are currently translating toward clinic. We introduce the adult human RPE stem cell (hRPESC) as an alternative RPE source. Polarized monolayers of adult hRPESC-derived RPE grown on polyester (PET) membranes had near-native characteristics. Trephined pieces of RPE monolayers on PET were transplanted subretinally in the rabbit, a large-eyed animal model. After 4 days, retinal edema was observed above the implant, detected by spectral domain optical coherence tomography (SD-OCT) and fundoscopy. At 1 week, retinal atrophy overlying the fetal or adult transplant was observed, remaining stable thereafter. Histology obtained 4 weeks after implantation confirmed a continuous polarized human RPE monolayer on PET. Taken together, the xeno-RPE survived with retained characteristics in the subretinal space. These experiments support that adult hRPESC-derived RPE are a potential source for transplantation therapies.

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for the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group IMPORTANCE Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient.OBJECTIVE To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab.DESIGN, SETTING, AND PARTICIPANTS This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized.INTERVENTIONS All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. MAIN OUTCOMES AND MEASURESThe primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee.RESULTS Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group.CONCLUSIONS AND RELEVANCE This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab.

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ABSTRACT.Purpose: To assess the effectiveness of consecutive intravitreal injections of recombined tissue plasminogen activator (rtPA), expansile gas and bevacizumab in eyes with acute subretinal haemorrhage (SRH). Methods: A retrospective, non-randomized consecutive case series included 19 eyes in 19 patients with SRH related to exudative age-related macular degeneration (AMD). The initial size of the subfoveal SRH was 1-3 disc diameters. Each patient received a triple procedure using 0.05 ml rtPA (50 lg), 0.3 ml of sulphur hexafluoride (SF6) gas and 0.05 ml bevacizumab (1.25 mg). Lesion size, location of the SRH and early treatment in diabetic retinopathy study (ETDRS) visual acuity were evaluated pretreatment as well as 1 and 3 months after the procedure. Results: At the initial presentation, the patients' mean age was 77 years (range 63-88 years) and the mean duration of symptoms was 9.3 days (range 4-12 days). The mean visual acuity pretreatment (20 ⁄ 133) improved significantly to 20 ⁄ 86 at 1 month and to 20 ⁄ 74 at 3 months. The mean ETDRS visual acuity improved from baseline by 2.1 lines at 1 month (Wilcoxon ranks test; P < 0.005) and 3.7 lines at 3 months after treatment (Wilcoxon ranks test; P < 0.005). None of our patients had reading visual acuity prior to treatment, with visual acuity below 0.3. One month after the triple procedure, 25% of our patients had reading visual acuity ( ‡ 0.4); at 3 months, the figure was 35%. A successful inferior displacement of the SRH was achieved in 17 ⁄ 19 eyes. Eyes with elevated intraocular pressure were treated immediately by a corneal paracentesis. Conclusion: The intravitreal application of rtPA, gas and bevacizumab appears to be beneficial and well tolerated in the treatment of SRH in the short term. The triple approach seems a logical alternative to the current combined dual approach in limiting the progression of the underlying disease and achieving better visual outcome. Further randomized evaluations are warranted.

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Ranibizumab PRN resulted in greater visual acuity (VA) gains in macular oedema following BRVO compared with single-dose dexamethasone over a 6-month study period, observed from month 3, when administered according to their European label. In clinical practice, retreatment with dexamethasone may be required prior to this point.