Novel treatment for PXE: Recombinant ENPP1 enzyme therapy.

Mol Ther

Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address:

Published: November 2024

AI Article Synopsis

  • Pseudoxanthoma elasticum (PXE) is a genetic disorder caused by mutations in the ABCC6 gene, leading to impaired levels of a calcification inhibitor, plasma inorganic pyrophosphate (PPi).
  • Recent studies show that a treatment called INZ-701 can restore PPi levels and prevent calcification in animal models, while the new enzyme therapy BL-1118 demonstrates effective results in increasing PPi levels and reducing ectopic calcification in mice.
  • BL-1118's potential as a second-generation treatment suggests it may provide better efficacy than the ongoing first-generation therapies, with promising results from pharmacokinetic and pharmacodynamic studies.

Article Abstract

Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of a potent endogenous calcification inhibitor, plasma inorganic pyrophosphate (PPi); the deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1 that generates PPi and is now in clinical trials, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of Abcc6mice. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6 mice. When Abcc6 mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 h. When Abcc6 mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising second generation enzyme therapy for PXE, the first generation of which is currently in clinical testing.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573614PMC
http://dx.doi.org/10.1016/j.ymthe.2024.09.028DOI Listing

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