Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

Abstract

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point.

Keywords: arterial calcification due to CD73 deficiency; ectopic mineralization disorders; generalized arterial calcification of infancy; pseudoxanthoma elasticum; therapy development.

Figure 1

Clinical features and ectopic mineralization in pseudoxanthoma elasticum (PXE), generalized arterial calcification of infancy (GACI), and arterial calcification due to CD73 deficiency (ACDC). PXE is characterized by late-onset cutaneous manifestations, including loose and inelastic skin (A). Biopsy of the affected area of skin reveals accumulation of pleomorphic elastotic material in mid dermis as visualized by Verhoeff-van Gieson stain (B). The aberrant elastotic material demonstrates calcification, as shown by von Kossa stain (C). Some patients with GACI manifest with early cutaneous findings similar to PXE (D; boxed area in D is enlarged in E), and histopathology reveals evidence of ectopic mineralization of skin elastic fibers in the dermis (F). In classic cases of GACI, the patients demonstrate severe vascular mineralization with intimal hypoplasia (G), and the patients often die during the early postnatal period. ACDC affects primarily elderly individuals with periarticular calcification (H, arrows), and extensive vascular calcification in the lower extremities (I). (The figures were adopted, with permission, from the following publications: [2,3,4].

Figure 2

Milestones in PXE research, preclinical studies, and early clinical trials. The events are reported in chronological order and refer to the year of publication, except inorganic pyrophosphate trial (asterisk), which is registered as a clinical trial at early stages of development.