2020
DOI: 10.1002/jbmr.4315
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INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice

Abstract: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss‐of‐function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal‐recessive hypophosphatemic rickets type 2… Show more

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Cited by 23 publications
(13 citation statements)
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“…However, the use of burosumab in ARHR2 patients is currently not recommended since it is not approved for this condition, and there exist concerns about worsening of ectopic calcification (18,19). ENPP1 replacement therapy, currently being developed in animal models, may be a future treatment for ARHR2 (13,20).…”
Section: Discussionmentioning
confidence: 99%
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“…However, the use of burosumab in ARHR2 patients is currently not recommended since it is not approved for this condition, and there exist concerns about worsening of ectopic calcification (18,19). ENPP1 replacement therapy, currently being developed in animal models, may be a future treatment for ARHR2 (13,20).…”
Section: Discussionmentioning
confidence: 99%
“…Although no evidence of arterial calcification was observed in this case, loss-of-function variants in ENPP1 are also known to be associated with GACI (OMIM 208000), a life-threatening disease characterized by calcification of medium and large arteries (2). ENPP1 regulates mineralization by suppressing hydroxyapatite crystal deposition via hydrolysis of adenosine triphosphate into adenosine monophosphate and PPi (20). Therefore, ENPP1deficiency results in pathological calcification and overmineralization in vessels and soft tissues, resulting in GACI.…”
Section: Discussionmentioning
confidence: 99%
“…The Abcc6 −/− mice began treatment at 6 weeks of age, the earliest stages of ectopic calcification in these mice 23 . To suppress the potential immune response to INZ‐701, all mice were administered intraperitoneal 40 μg GK‐1.5, an anti‐CD4 monoclonal antibody (Thermo Fisher Scientific), at Day 1 followed by a weekly intraperitoneal boost of 25 μg GK‐1.5, as described previously for Enpp1 asj/asj mice 20,21 . Mice were maintained on the standard rodent diet and sacrificed after 2 or 8 weeks of treatment.…”
Section: Experimental Designmentioning
confidence: 99%
“…INZ-701, a soluble recombinant ENPP1 enzyme, normalized plasma PPi levels by utilizing circulating ATP as a substrate, and subsequently prevented mortality, vascular calcification and defects of bone mineralization in the Enpp1 asj/asj mouse model of ENPP1 deficiency. 20,21 The efficacy of INZ-701 on ectopic calcification in PXE, a PPi deficiency disorder due to deficiency in ABCC6 which works upstream of ENPP1, has yet to be demonstrated. Normalization of plasma PPi levels in the Abcc6 −/− mice via genetic overexpression of human ENPP1 transgene significantly reduced ectopic calcification, 22 suggesting that INZ-701, the ENPP1 protein therapeutic, could be efficacious for PXE.…”
Section: Backg Rou N Dmentioning
confidence: 99%
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