Abstract
ABSTRACTGeneralized arterial calcification of infancy (GACI) is a rare, life-threatening disorder caused by loss-of-function mutations in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), which normally hydrolyzes extracellular ATP into AMP and pyrophosphate (PPi). The disease is characterized by extensive arterial calcification and stenosis of large- and medium-sized vessels, leading to vascular-related complications of hypertension and heart failure. There is currently no effective treatment available, but bisphosphonates – nonhydrolyzable PPi analogs – are being used off-label to reduce arterial calcification, although this has no reported impact on the hypertension and cardiac dysfunction features of GACI. In this study, the efficacy of a recombinant human ENPP1 protein therapeutic (rhENPP1) was tested in Enpp1asj-2J homozygous mice (Asj-2J or Asj-2J hom), a model previously described to show extensive mineralization in the arterial vasculature, similar to GACI patients. In a disease prevention study, Asj-2J mice treated with rhENPP1 for 3 weeks showed >95% reduction in aorta calcification. Terminal hemodynamics and echocardiography imaging of Asj-2J mice also revealed that a 6-week rhENPP1 treatment normalized elevated arterial and left ventricular pressure, which translated into significant improvements in myocardial compliance, contractility, heart workload and global cardiovascular efficiency. This study suggests that ENPP1 enzyme replacement therapy could be a more effective GACI therapeutic than bisphosphonates, treating not just the vascular calcification, but also the hypertension that eventually leads to cardiac failure in GACI patients.
Highlights
Generalized arterial calcification of infancy (GACI) is a severe, rare disease characterized by excessive calcification and stenosis of large- and medium-sized arteries
We investigated the potential use of ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) enzyme replacement therapy (ERT) for the treatment of GACI
We examined ENPP1 ERT in Enpp1asj-2J (Asj-2J) mice, a model that is more severe than the al used Enpp1asj mice (Asj) model, possibly due to its ∼40 kb deletion/74 bp insertion in an intron/3′UTR region and a different strain background (Li et al, 2014)
Summary
Generalized arterial calcification of infancy (GACI) is a severe, rare disease characterized by excessive calcification and stenosis of large- and medium-sized arteries. Arterial stenosis occurs due to severe myointimal proliferation and reduced vascular elasticity, and. Other hallmarks of the disease include cardiomegaly, respiratory distress and cyanosis. Affected arteries in GACI include the aorta, coronary arteries, pulmonary arteries and renal arteries (Chong and Hutchins, 2008; Rutsch et al, 2008). Histological examination of affected arteries often shows calcium deposition in the internal elastic lamina and fibrointimal hyperplasia, both of which can contribute to luminal narrowing (Moran, 1975; Morton, 1978; Witzleben, 1970)
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