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ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy.
Dis Model Mech. 2018 10 08; 11(10)DM

Abstract

Generalized 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.

Authors+Show Affiliations

Alexion Pharmaceuticals, Lexington, MA 02421, USA tayeba_khan@yahoo.com.Alexion Pharmaceuticals, Lexington, MA 02421, USA.Alexion Pharmaceuticals, New Haven, CT 06510, USA.Alexion Pharmaceuticals, Lexington, MA 02421, USA.Alexion Pharmaceuticals, Lexington, MA 02421, USA.Alexion Pharmaceuticals, New Haven, CT 06510, USA.Alexion Pharmaceuticals, New Haven, CT 06510, USA.Alexion Pharmaceuticals, Lexington, MA 02421, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30158213

Citation

Khan, Tayeba, et al. "ENPP1 Enzyme Replacement Therapy Improves Blood Pressure and Cardiovascular Function in a Mouse Model of Generalized Arterial Calcification of Infancy." Disease Models & Mechanisms, vol. 11, no. 10, 2018.
Khan T, Sinkevicius KW, Vong S, et al. ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy. Dis Model Mech. 2018;11(10).
Khan, T., Sinkevicius, K. W., Vong, S., Avakian, A., Leavitt, M. C., Malanson, H., Marozsan, A., & Askew, K. L. (2018). ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy. Disease Models & Mechanisms, 11(10). https://doi.org/10.1242/dmm.035691
Khan T, et al. ENPP1 Enzyme Replacement Therapy Improves Blood Pressure and Cardiovascular Function in a Mouse Model of Generalized Arterial Calcification of Infancy. Dis Model Mech. 2018 10 8;11(10) PubMed PMID: 30158213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy. AU - Khan,Tayeba, AU - Sinkevicius,Kerstin W, AU - Vong,Sylvia, AU - Avakian,Arlen, AU - Leavitt,Markley C, AU - Malanson,Hunter, AU - Marozsan,Andre, AU - Askew,Kim L, Y1 - 2018/10/08/ PY - 2018/05/23/received PY - 2018/08/21/accepted PY - 2018/8/31/pubmed PY - 2019/5/28/medline PY - 2018/8/31/entrez KW - Enpp1 KW - Enzyme replacement therapy KW - GACI KW - Hypertension KW - Vascular calcification JF - Disease models & mechanisms JO - Dis Model Mech VL - 11 IS - 10 N2 - Generalized 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. SN - 1754-8411 UR - https://www.unboundmedicine.com/medline/citation/30158213/ENPP1_enzyme_replacement_therapy_improves_blood_pressure_and_cardiovascular_function_in_a_mouse_model_of_generalized_arterial_calcification_of_infancy_ L2 - http://dmm.biologists.org/cgi/pmidlookup?view=long&pmid=30158213 DB - PRIME DP - Unbound Medicine ER -