ESPE Yearbook of Paediatric Endocrinology

Abstract: Dis Model Mech. 2018 Oct 1; 11(10): dmm035691.

In brief: Generalized arterial calcification of infancy (GACI) is a severe, rare disease characterized by excessive calcification of large and medium sized arteries caused by homozygous loss-of-function mutations in ENPP1. Here, in Enpp1 deficient mice, treatment with recombinant human ENPP1 protein was more effective than bisphosphonates to resolve not only the vascular calcification, but also the hypertension that eventually leads to cardiac failure in GACI patients.

Comment: Generalized arterial calcification of infancy (GACI) is a severe, rare disease characterized by excessive calcification and stenosis of large- and medium-sized arteries. Approximately 70% of GACI cases are associated with loss-of-function mutations in ENPP1, an ectonucleotide pyrophosphatase/phosphodiesterase 1 that produces inorganic pyrophosphate (PPi). PPi is an inhibitor of tissue mineralization critical to prevent mineralization of non-skeletal tissues. Disease onset of GACI can vary, but the majority of patients present in utero through 6 months of age. GACI is associated with a high mortality rate, with death typically occurring from vascular occlusion and additional cardiovascular complications. If left untreated, GACI results in 85% lethality by 6 months of age. A retrospective case study by Rutsch et al. demonstrated that although bisphosphonate treatment reduced the mortality rate during infancy to 35%, 7/17 patients treated with bisphosphonates still died during infancy.

In this study, authors examined rhENPP1 in Asj-2J mice, which have a phenotype that is more similar to the human disease than that of previously studied mouse models. Similar to humans with GACI, Asj-2J mice spontaneously develop severe disease and exhibit elevated systemic blood pressure, which is believed to be the cause of death in GACI patients. The authors observed significant improvements in both vascular calcification and cardiovascular function in Asj-2J mice following treatment with rhENPP1. Since hypertension is the leading cause of cardiac failure in GACI patients, rhENPP1 ERT could be important in resolving the disease more effectively and in a greater number of patients than bisphosphonates.

Further studies will be necessary to examine the therapeutic window for rhENPP1 ERT in GACI patients, and whether it has capabilities beyond being used as a disease prevention tool. Calcification reversal will likely be more difficult to achieve owing to the pronounced stability and insolubility of hydroxyapatite. The role of rhENPP1 in calcification regression will need to be evaluated in the future but will likely depend on the extent of calcification and will likely require long-term treatment.