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

• Applicant: Privatdozentin Dr. Kristina Pfau
• Subject Area: Ophthalmology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532367710

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.

• DFG Programme: Research Grants