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

弹性假黄色瘤（PXE）是一种常染色体隐性遗传的多系统疾病，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Bruch膜（BrM）矿化，BrM是一层薄薄的五层细胞外基质，将视网膜色素上皮（RPE）与脉络膜分开。BrM作为一个关键的机械支架，调节RPE和体循环之间的交换。因此，BrM的通透性对营养物质的运输和向光感受器的供应具有重要意义。BrM弹性纤维在PXE中逐渐钙化，从视神经周围开始，并在一生中向周围扩散。目前，没有治疗PXE的方法。然而，旨在减缓疾病进展的有希望的方法正在出现。这些方法包括全身和局部治疗（clinicaltrials.gov标识符NCT04868578， NCT04868578, NCT05030831, NCT05569252）。正在进行的和过去的试验主要集中在基于血管学的临床报告结果评估（ClinROs），如基于计算机断层扫描（CT）的动脉钙化，或重复的皮肤活检。然而，这些ClinROs短期检测变化的能力尚未建立。此外，FDA等监管机构表示更倾向于与患者报告的结果测量（PROMs）或绩效结果测量直接相关的clinro。最佳矫正视力（BCVA）是最广泛使用的眼科结果测量指标，此前已应用于PXE的介入性试验。但在这种疾病中，BCVA并不是矿化的衡量标准。相反，PXE的BCVA主要反映继发性并发症，如新生血管形成引起的渗出或RPE萎缩。因此，评估早期PXE治疗方案的一个主要挑战是缺乏可靠的结果测量来测试未来治疗方案的有效性。理想情况下，pxe特异性眼科临床试验终点应该(i)反映BrM矿化的进展，（ii）适用于从年轻患者到中枢萎缩患者的广泛疾病严重程度。作为治疗试验的下一步，候选ClinROs的重测可靠性和随时间的进展必须在pxe特异性环境中建立。此外，如果未来的干入性试验应该关注特定的PXE亚群，如双等位基因完全丧失ABCC6蛋白功能的患者，对基因型贡献的分析是至关重要的。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，并比较它们在早期疾病阶段和进展疾病阶段检测变化的能力，以及基因型和血清标记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.