Table 2.
Interventional preclinical studies and early clinical trials for PXE, GACI, and ACDC, published and on-going.
| Treatment | Rationale/Target | Diagnosis | Publications |
|---|---|---|---|
| Preclinical trials | |||
| Sevelamer hydrochloride | Phosphate binder | PXE | [26] |
| Magnesium | Competes with calcium to prevent calcium hydroxyapatite crystal formation | PXE | [27,28,29] |
| GACI | [30] | ||
| Statin | Lipid-lowering drug | PXE | [31] |
| Chaperone therapy | Corrects the trafficking defect of misfolded ABCC6 protein | PXE | [15,32,33,34] |
| PTC-read through drug | Read-through of PTC codons | PXE | [35] |
| Bisphosphonates | Stable nonhydrolyzable PPi analogs | PXE | [15,36,37] |
| GACI | [38,39] | ||
| PPi administration | Correction of reduced plasma PPi levels in PXE and GACI | PXE | [15,16,40] |
| GACI | [16] | ||
| ENPP1 protein replacement | ENPP1 is the principal enzyme that generates PPi | PXE | [41] |
| GACI | [42,43] | ||
| TNAP inhibitor | TNAP is the enzyme that breaks down PPi | PXE | [44,45] |
| GACI | [44] | ||
| Gene therapy | ABCC6 gene therapy to reconstitute hepatic ABCC6 | PXE | [46] |
| Clinical trials | |||
| Aluminum hydroxide 1) | Phosphate binder | PXE | [47] |
| VEGF antagonists 2) | Bevacizumab and ranibizumab, inhibitors of vascular endothelial growth factor for the treatment of choroidal neovascularization | PXE | [48] |
| Sevelamer hydrochloride 3) | Phosphate binder | PXE | [49] |
| Magnesium 4) | Prevention of ectopic mineralization | PXE | [50] |
| Bisphosphonates 5) | Stable nonhydrolyzable PPi analogs | PXE | [51,52] |
| GACI | [18,53,54] | ||
| ACDC | NCT01585402 * | ||
| VEGF antagonist 6) | Aflibercept, an inhibitor of vascular endothelial growth factor for the treatment of choroidal neovascularization | PXE | [55] |
| Sodium thiosulfate 7) | Antioxidant properties and chelation of calcium to form soluble calcium thiosulfate complexes | PXE | [56] |
| PPi administration | Correction of reduced plasma PPi levels in PXE and GACI | PXE | NCT04441671 * |
PXE, pseudoxanthoma elasticum; GACI, generalized arterial calcification of infancy; ACDC, arterial calcification due to deficiency of CD73. * ClinicalTrials.gov Identifier; 1) Six PXE patients, 1-year follow-up. Three patients showed significant clinical improvement and histopathologic regression of calcification in the skin lesions. No deterioration of eye disease was observed in any of the six patients; 2) Long-term results of intravitreal antivascular endothelial growth factors, bevacizumab and ranibizumab, in the management of choroidal neovascularization in nine PXE patients with angioid streaks. During the mean follow-up period of 28.6 months, visual acuity was either improved or stabilized in all patients without complications; 3) Randomized, double-blind, placebo-controlled, prospective clinical study in 40 patients with PXE. While reduction in both calcification levels and clinical scores of the skin were noted, the differences were not statistically significant compared with placebo; 4) The NCT01525875 magnesium trial was a randomized, double-blind, placebo-controlled prospective trial that evaluated the effect of oral magnesium oxide (MgO) versus placebo on the skin and eyes in 44 PXE patients. Although not statistically significant, the treatment group was found to have decreased elastic fiber calcification in the skin. No significant treatment effect was observed in the ophthalmologic outcomes; 5) The Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial (NTR5180) tested the effects of etidronate in 74 PXE patients with leg arterial calcifications (mean age: 57 years, range 48–66) randomly assigned to etidronate or placebo. During 12 months of follow-up, etidronate reduced arterial calcification and subretinal neovascularization events without important safety issues; 6) The NCT02537054 trial was a 12-month prospective, open-label, uncontrolled, nonrandomized interventional clinical trial testing the effects of 2 mg intravitreal aflibercept for treatment of choroidal neovascularization (CNV) secondary to angioid streaks, in 15 PXE patients (mean age: 53 years, range 22–65). After 12 months of treatment, aflibercept improved or stabilized best corrected visual acuity (BCVA), central retinal thickness (CRT), retinal sensitivity, and vision-related quality of life in the majority of patients; 7) Intravenous sodium thiosulfate was administered in a young patient with PXE-like syndrome. This 11-year old patient, with severe early-onset systemic calcifications occurring in the skin and in the arteries, demonstrated radical improvement in asthaenia, anorexia and pre-/postprandial pain and calcific stenosis after six months of treatment.