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Abstract：
BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).
摘要：
背景视网膜血管病变合并脑白质脑病和全身表现(RVCL-S)是一种罕见的,常染色体显性,普遍致命的疾病没有有效的治疗选择。本研究探讨了crizanlizumab的安全性和初步疗效，一种抗P-选择素的人源化单克隆抗体被批准用于预防镰状细胞危象，在RVCL-S患者中减缓视网膜非灌注和保持视力。METHODSEleven具有证实的外切核酸酶3prime修复外切核酸酶1（TREX1）突变的RVCL-S患者在2年内每月接受crizanlizumab输注。该研究通过荧光素血管造影术测量了3个视网膜区域和整个视网膜内的非灌注指数，视敏度,眼内压（IOP），和光学相干层析成像中心子场厚度（CST）在基线，1年,和2年。进行混合重复测量分析以评估进展速率和相对于基线的变化。结果SEleven参与者接受了crizanlizumab输注。所有参与者对crizanlizumab的耐受性都很好，11人中有8人（72.7%）报告了轻微的不良反应，如恶心，疲劳,和胃肠道症状。第1年视网膜总无灌注变化为7.22%[4.47,9.97],第2年为-0.69%[-4.06,2.68](P<0.001)。在中部外围，第1年的非灌注变化为10.6%[5.1,16.1],第2年为-0.68%[-3.98,5.35](P<0.01),在治疗的第二年，未灌注的进展有所减少。视敏度,IOP,CST保持稳定。结论Crizanlizumab具有可接受的安全性。这些结果显示了在RVCL-S和类似小血管疾病的更大研究中检查crizanlizumab以及使用视网膜作为全身性疾病的生物标志物的有希望的潜力。试验注册ClinicalTrials.govNCT04611880。基金会Clayco基金会；德纳多教育与研究基金会赠款；JeffreyT.Fort创新基金；SitemanRetina研究基金；防止失明研究公司的无限制赠款；国家心脏，肺，和血液研究所（NHLBI），美国国立卫生研究院（R01HL129241）；国家神经疾病和中风研究所（NINDS），NIH(RF1NS116565)。
