Natural History and Structural Consequences of a Diseased Bruch’s Membrane in Pseudoxanthoma Elasticum (PXE)

弹性纤维性假黄瘤（PXE）是一种常染色体隐性遗传性多系统疾病，导致弹性纤维钙化。受影响的组织包括皮肤、心血管系统和眼睛。在眼睛中，PXE导致布鲁赫膜（Bruch’s membrane，BrM）的矿化，布鲁赫膜是将视网膜色素上皮（retinal pigment epithelium，RPE）与脉络膜分离的薄的细胞外基质的五层。BrM作为关键的机械支架，调节RPE和体循环之间的交换。因此，BrM的不受阻碍的渗透性对于营养素运输和供应到光感受器是非常重要的。BrM弹性纤维在PXE中逐渐钙化，从视神经周围开始，并在整个生命过程中向外周扩散。目前，没有针对PXE的治疗方法。然而，旨在减缓疾病进展的有希望的方法现在正在出现。这些方法包括全身和局部治疗（clinicaltrials.gov标识符NCT 04868578、NCT 04868578、NCT 05030831、NCT 05569252）。正在进行和过去的试验主要关注基于血管病学的临床医生报告结局评估（ClinRO），例如基于计算机断层扫描（CT）的动脉钙化或重复皮肤活检。然而，这些ClinRO尚未建立检测变化的短期能力。此外，FDA等监管机构表示倾向于使用与患者报告结局指标（PROM）或性能结局指标直接相关的ClinRO。最佳矫正视力（BCVA）-最广泛使用的眼科结局指标-先前已应用于PXE的干预性试验。但在这种疾病中，BCVA不是矿化的衡量标准。相反，PXE中的BCVA主要反映继发性并发症，如由于新血管形成或RPE萎缩引起的渗出。因此，评估早期PXE治疗选择的主要挑战是缺乏可靠的结果测量来测试未来治疗选择的功效。理想情况下，PXE特异性眼科临床试验终点应（i）反映BrM矿化的进展，以及（ii）适用于从年轻患者到中枢性萎缩患者的广泛疾病严重程度。作为治疗试验的合理下一步，必须在PXE特定环境中确定候选ClinRO的复检可靠性和随时间推移的进展。此外，基因型贡献的分析是必要的，以澄清，如果未来的干预性试验应该集中在一个特定的PXE亚群，如患者的ABCC 6蛋白功能的双等位基因完全丧失。总之，该项目的总体目标是确定可用于临床试验的疾病特异性终点，并比较它们检测早期疾病阶段变化的能力，疾病进展阶段，以及基因型和血清标志物对这些参数的影响。

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystemic disease leading to the calcification of elastic fibers. Affected tissues include the skin, the cardiovascular system, and the eye. In the eye, PXE leads to the mineralization of Bruch’s membrane (BrM), a thin pentalayer of extracellular matrix separating the retinal pigment epithelium (RPE) from the choroid. The BrM serves as a critical mechanical scaffold and regulates the interchange between the RPE and the systemic circulation. Therefore, an unhindered permeability of BrM is of high importance for nutrient transport and supply to the photoreceptors. BrM elastic fibers progressively calcify in PXE, starting around the optic nerve and spreading toward the periphery throughout life. Currently, no treatment is available for PXE. However, promising approaches aiming at slowing the disease progression are now emerging. These approaches include both systemic and local therapies (clinicaltrials.gov identifier NCT04868578, NCT04868578, NCT05030831, NCT05569252). Ongoing and past trials focus primarily on angiology-based clinician-reported outcome assessments (ClinROs) such as computer tomography (CT)-based arterial calcification, or repeated skin biopsies. However, the short-term ability to detect change is not established for those ClinROs. In addition, regulatory agencies such as the FDA expressed a preference for ClinROs that are directly linked to patient-reported outcome measures (PROMs) or performance outcome measures. Best-corrected visual acuity (BCVA) - the most widely used ophthalmic outcome measure - has been previously applied in interventional trials for PXE. But in this disease, BCVA is not a measure of mineralization. Instead, BCVA in PXE reflects mostly secondary complications like exudation due to neovascularization, or RPE atrophy. Accordingly, a major challenge in evaluating therapeutic options in early PXE is that reliable outcome measures are lacking to test the efficacy of future therapeutic options. A PXE-specific ophthalmic clinical trial endpoint should ideally be (i) reflective of the progression of BrM mineralization, and (ii) applicable across a wide range of disease severities ranging from young patients to patients with central atrophy. As the logical next step toward a therapeutic trial, the retest reliability and progression over time of the candidate ClinROs must be established in a PXE-specific setting. Further, analyses of the genotype contribution are essential to clarify, if future interventional trials should focus on a specific PXE sub-population, such as patients with bi-allelic complete loss of ABCC6 protein function. In summary, the overarching aim of this project is to identify disease-specific endpoints that can be used in clinical trials and compare them regarding their ability-to-detect change in early disease stages, progressed disease stages, and the influence of the genotype and serum markers on these parameters.