John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, and.
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Clin Invest. 2024 May 7;134(12):e180916. doi: 10.1172/JCI180916.
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).
背景视网膜血管病变伴脑白质病和全身表现（RVCL-S）是一种罕见的常染色体显性遗传疾病，普遍致命，目前尚无有效的治疗方法。本研究探讨了针对 P-选择素的人源化单克隆抗体crizanlizumab 在减缓视网膜无灌注和保护 RVCL-S 患者视力方面的安全性和初步疗效。
方法11 名确诊有外切核酸酶 3′端修复外切核酸酶 1（TREX1）突变的 RVCL-S 患者接受了 2 年的每月crizanlizumab 输注。该研究通过荧光素血管造影测量了 3 个视网膜区域内的无灌注指数和整个视网膜、视力、眼内压（IOP）和光学相干断层扫描中央视网膜厚度（CST），在基线、1 年和 2 年时进行测量。采用混合重复测量分析评估进展率和从基线的变化。
结果11 名参与者接受了 crizanlizumab 输注。所有参与者均能很好地耐受 crizanlizumab，其中 8 名（72.7%）报告有轻度不良反应，如恶心、疲劳和胃肠道症状。第 1 年全视网膜无灌注的变化为 7.22%[4.47，9.97]，第 2 年为-0.69%[-4.06，2.68]（P<0.001）。在中周部，第 1 年无灌注的变化为 10.6%[5.1，16.1]，第 2 年为-0.68%[-3.98，5.35]（P<0.01），表明在治疗的第二年无灌注进展减少。视力、IOP 和 CST 保持稳定。
结论crizanlizumab 具有可接受的安全性。这些结果表明，crizanlizumab 在更大规模的 RVCL-S 和类似小血管疾病研究以及将视网膜作为全身疾病的生物标志物方面具有潜在的应用前景。
试验注册ClinicalTrials.gov NCT04611880。
资助Clayco 基金会；DeNardo 教育和研究基金会赠款；Jeffrey T. Fort 创新基金；Siteman 视网膜研究基金；美国国家眼科研究所（Research to Prevent Blindness Inc.）的无限制赠款；美国国立卫生研究院（NHLBI）国家心脏、肺和血液研究所（R01HL129241）；美国国立卫生研究院（NINDS）国家神经疾病与卒中研究所（RF1NS116565）。
