Journal
EXPERIMENTAL DERMATOLOGY
Volume 31, Issue 7, Pages 1095-1101Publisher
WILEY
DOI: 10.1111/exd.14587
Keywords
animal model; ectopic calcification; inorganic pyrophosphate; INZ-701; pseudoxanthoma elasticum
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Funding
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R21AR077332, R01AR072695]
- Inozyme Pharma
- Boston
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This study found that restoring plasma PPi levels can prevent ectopic calcification in a mouse model of Pseudoxanthoma elasticum (PXE). INZ-701 increases plasma ENPP1 activity and PPi levels, leading to significantly reduced calcification in the muzzle skin of the mice.
Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ-701, a recombinant human ENPP1 protein, the principal PPi-generating enzyme, prevents ectopic calcification in an Abcc6(-/-) mouse model of PXE. Abcc6(-/-) mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ-701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ-701 at both doses increased steady-state plasma ENPP1 activity and PPi levels. In the 8-week treatment study, histopathologic examination and quantification of the calcium content in INZ-701-treated Abcc6(-/-) mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin-A. These results suggest that INZ-701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.
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