ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized
Tayeba Khan1, Kerstin W Sinkevicius2, Sylvia Vong3
1Alexion Pharmaceuticals, Lexington, MA 02421, USA tayeba_khan@yahoo.com.
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 Enpp1 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.
Insights
Enzyme replacement therapy using recombinant human ENPP1 (rhENPP1) effectively treats arterial calcification and hypertension in a mouse model of Generalized Arterial Calcification of Infancy (GACI). This offers a promising new therapeutic approach for GACI patients.
Area of Science:
- Genetics and rare diseases
- Vascular biology and pathology
- Biochemistry and enzyme therapeutics
Background:
- Generalized Arterial Calcification of Infancy (GACI) is a rare, fatal disorder caused by ENPP1 gene mutations, leading to severe arterial calcification, hypertension, and heart failure.
- Current treatments like bisphosphonates target calcification but do not address hypertension or cardiac dysfunction in GACI.
- Extracellular ATP hydrolysis by ENPP1 is crucial for preventing vascular mineralization.
Purpose of the Study:
- To evaluate the therapeutic efficacy of recombinant human ENPP1 protein (rhENPP1) in a mouse model of GACI (Enpp1 homozygous mice).
- To assess rhENPP1's impact on arterial calcification, hypertension, and cardiac function in the GACI mouse model.
Main Methods:
- Treatment of Enpp1 homozygous mice with rhENPP1.
- Assessment of aortic calcification reduction after 3 weeks of rhENPP1 treatment.
- Evaluation of hemodynamics and echocardiography to measure cardiovascular function after 6 weeks of rhENPP1 treatment.
Main Results:
- rhENPP1 treatment resulted in over 95% reduction in aortic calcification in treated mice.
- Six weeks of rhENPP1 therapy normalized elevated arterial and left ventricular pressures.
- Significant improvements were observed in myocardial compliance, contractility, cardiac workload, and overall cardiovascular efficiency.
Conclusions:
- rhENPP1 enzyme replacement therapy is a potentially superior treatment for GACI compared to bisphosphonates.
- rhENPP1 effectively addresses both vascular calcification and the associated hypertension and cardiac dysfunction in GACI.
- This study supports rhENPP1 as a promising therapeutic candidate for treating Generalized Arterial Calcification of Infancy.
Related Concept Videos
01:30Continuous Renal Replacement Therapy
01:15Assessment of blood pressure in brachial artery(one-step method)
Prepare for the Procedure:
01:23Assessment of blood pressure in brachial artery(two-step method)
01:24Blood Pressure
01:30Blood Pressure
The average BP in an adult is typically around 120/80 mmHg (millimeters of mercury). In this measurement, the numerator (120) indicates the systolic pressure, which is the pressure in the arteries during the contraction of the heart's ventricles as blood is expelled. The denominator (80) represents the...
01:26Extracorporeal Removal of Drugs: Continuous Renal Replacement Therapy