Treatment of ENPP1 deficiency and ABCC6 deficiency in infants

Abstract

The present disclosure provides, among other things, specific doses of an ENPP1 agent for in vivo treatment of an ENPP1 deficiency, such as for treatment of Generalized Arterial Calcification of Infancy (GACI), Hypopyrophosphatemia, Autosomal Recessive Hypophosphatemic Rickets 2 (ARHR2), PXE and other diseases resulting from pathological calcification, ENPP1 deficiency, ABCC6 deficiency such as diseases or disorders involving ectopic calcification of soft tissue in an infant of age between of greater than 30 minutes but less than 12 months.

Description

[0001]Atty. Docket No.4427-12602 TREATMENT OF ENPP1 DEFICIENCY AND ABCC6 DEFICIENCY IN INFANTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.63 / 655,302 entitled “TREATMENT OF ENPP1 DEFICIENCY AND ABCC6 DEFICIENCY IN INFANTS” filed on June 3, 2024, the content of which is herein incorporated by reference in its entirety. FIELD The field of the invention relates to treatment of ENPP1 deficiency and ABCC6 deficiency by enzyme replacement. SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically as a WIPO Standard ST.26 XML file via Patent Center, created on June 2, 2025, is entitled “4427-12602.xml” and is 124 KB in size. The sequence listing is incorporated herein by reference in its entirety. BACKGROUND Calcification in biological systems is a complex process by which calcium salts are maintained at higher concentrations in noncirculating matrices than in regional circulating humoral or other mobile fluids. The principal result of normal calcification is the concentration of calcium and associated inorganic salts in crystalline patterns of similar arrangement and chemical composition in specialized intercellular matrices, all of which might vary among the different species. The net effect of pathological calcification is the concentration of calcium and associated inorganic salts with a greater-than-normal range in chemical composition or diversity of pattern, not only in these specialized matrices but also in other intercellular, extracellular, and cellular materials leading to several disease states. Some common examples of disease states of pathological calcification include but are not limited to kidney and bladder stones, dental pulp stones, gall stones, salivary gland stones, chronic calculous prostatitis, testicular microliths, calcification in hemodialysis patients, atherosclerosis, malacoplakia, scleroderma (systemic sclerosis), calcinosis cutis, calcific aortic stenosis, calcific tendonitis, synovitis and arthritis, diffuse interstitial skeletal hyperostosis, juvenile dermatomyositis, Generalized Arterial Calcification of Infancy (GACI), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, calcification of atherosclerotic plaques, Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), Pseudoxanthoma elasticum (PXE), ankylosing spondylitis, hardening of the arteries, calciphylaxis, and systemic lupus erythematosus. ENPP1 Deficiency is a rare, genetic disorder caused by inactivating mutations in the ENPP1 gene that encodes the ENPP1 enzyme. ENPP1 is an integral transmembrane protein whose Atty. Docket No.4427-12602 extracellular domains carry pyrophosphatase and phosphodiesterase activities. ENPP1 converts extracellular ATP to inorganic pyrophosphate (PPi) and AMP. ENPP1 Deficiency causes hypopyrophosphatemia and hypoadenosinemia which, in turn, leads to ectopic (especially arterial) calcification (described in literature as Generalized Arterial Calcification of Infancy [GACI]), skeletal dysfunction secondary to rickets and osteomalacia (described in literature as Autosomal Recessive Hypophosphatemic Rickets 2 [ARHR2]) and occlusive neo-intimal proliferation. Beyond symptomatic and palliative interventions, no targeted therapy exists for this disease. Thus, ENPP1 Deficiency has a high unmet medical need. Infants with ENPP1 Deficiency have high mortality in the first 0 to 6 months of life and children and adults with ENPP1 Deficiency experience ongoing risk for organ calcification and dysfunction, debilitating rickets that progresses to osteomalacia in adulthood with severe bone and joint pain, fatigue, muscle weakness, and repeated bone fractures, all symptoms that lead to poor quality of life and function. Hypopyrophosphatemia causes a reactive increase in fibroblast growth factor 23 (FGF23) leading to hyperphosphaturia (the ENPP1 Deficiency “biochemical axis”), an essential feature in the pathophysiology of ENPP1 Deficiency. ENPP1 Deficiency is characterized biochemically by low plasma PPi levels and clinically characterized by vascular calcification in infants (GACI Type phenotype) and rickets (ARHR2 phenotype) post-infancy and intimal proliferation. GACI (generalized arterial calcification of infants) is a severe disease occurring in infants and involving extensive arterial calcification (Albright, et al., 2015, Nature Comm.10006). In infants who suffer from ENPP1 Deficiency, an acutely life-threatening phenotypic presentation can result, in which there is generalized arterial calcification and ultimately a high rate of mortality. Mortality is at the highest during infancy, ranging from 41% to 70%, and occurs predominantly in the first 6 months of life. (See Figure 1) ABCC6 deficiency is a rare, inherited, genetic inborn error of metabolism caused by mutations in the ABCC6 gene. ABCC6 deficiency is inherited as a recessive trait in which the genetic mutations result in decreased or absent activity of the ABCC6 protein (also known as MRP6 (multi-drug resistance protein 6), ATP-binding cassette sub-family C member 6 (ABCC6) and multi-specific organic anion transporter E (MOAT-E). The deficiency leads to low plasma levels of PPi and is associated with pathological mineralization in blood vessels and soft tissues throughout the body, resulting in significant morbidity, including blindness, life-threatening cardiovascular complications, and skin calcification throughout the body, resulting in significant morbidity, including blindness, life-threatening cardiovascular complications, and skin calcification. The pathological mineralization associated with ABCC6 deficiency is the result of ectopic calcification in elastic fibers, a component of connective tissue, which provides strength and flexibility to structures throughout the body. Ectopic calcification can affect function in elastic fibers in the eyes, blood vessels, and skin, and less frequently in other areas such as the digestive tract. (See Figure 6) Atty. Docket No.4427-12602 Mutations in ABCC6 cause pseudoxanthoma elasticum (PXE). The most common mutations, R1141X and 23-29del, account for about 25% of identified mutations. Le Saux O, et al. (2001). "A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum". Am. J. Hum. Genet.69 (4): 749–64. Pfendner EG, et al. (2007). "Mutation Detection in the ABCC6 Gene and Genotype-Phenotype Analysis in a Large International Case Series Affected by Pseudoxanthoma Elasticum". Journal of Medical Genetics.44 (10): 621–8. Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. Trip MD, et al. (2002). "Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease". Circulation.106 (7): 773–5. Deficiency of ABCC6 in mouse models of ischemia leads to larger infarcts, which can be rescued by ABCC6 overexpression. Mungrue IN, et al. (2011). "ABCC6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model". Arterioscler Thromb Vasc Biol.31 (12): 2806–12. Some infants with ABCC6 deficiency are diagnosed with a vascular calcification condition resembling the acute infantile form of ENPP1 deficiency. In older patients, ABCC6 deficiency presents as pseudoxanthoma elasticum, or PXE, a rare disorder in which individuals develop calcification of soft connective tissues, including in the eyes, cardiovascular system, and skin. Individuals with PXE often have abnormalities in the eyes, such as a change in the pigmented cells of the retina or angioid streaks that occur when tiny cracks form in Bruch’s membrane, the elastic membrane beneath the retina. Choroidal neovascularization — subsequent bleeding and scarring of the retina — may also occur, which, together with the damage to Bruch’s membrane, can cause vision loss. A recent report stated that 37 percent of PXE patients over the age of 50 experienced visual impairment and 15 percent were legally blind. (Risseeuw S, Ossewaarde-van Norel J, Klayer CCW, Colijn JM, Imhof SM, van Leeuwen R. Visual acuity in pseudoxanthoma elasticum. Retina.2019;39(8):1580-1587). Pathological mineralization of the vessels that carry blood from the heart to the rest of the body may cause other signs and symptoms of PXE. Ectopic calcification narrows blood vessels, particularly in the lower extremities, and leads to claudication, a condition characterized by cramping and pain during exercise due to decreased blood flow to the arms and legs. Individuals with PXE may also have yellowish bumps called papules on the neck, underarms, and other areas of the skin surrounding the joints. These papules are painful, can impair joint movement, and indicate a general, systemic, pathological process of soft tissue calcification. PPi is modulator of bone mineralization and a potent inhibitor of calcium hydroxyapatite crystal deposition and is essential for prevention of harmful soft tissue calcification. PPi functions as a potent inhibitor of ectopic tissue mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing the future growth of these crystals. ENPP1 Atty. Docket No.4427-12602 generates PPi via hydrolysis of nucleotide triphosphates (NTPs), Progressive Ankylosis Protein (ANK) transports intracellular PPi into the extracellular space, and Tissue Non-specific Alkaline Phosphatase (TNAP) removes PPi via direct hydrolysis of PPi into Pi. Ectopic tissue mineralization is associated with numerous human diseases, including chronic joint disease and acutely fatal neonatal syndromes. To prevent unwanted tissue calcification, factors that promote and inhibit tissue mineralization must be kept in tight balance. The balance of extracellular inorganic pyrophosphate (PPi) and phosphate (Pi) is an important regulator of ectopic tissue mineralization. The activity of the three extracellular enzymes -TNAP, ANK, and ENPP1 - tightly control the concentration of Pi and PPi. PPi is a regulator of biomineralization, inhibiting the formation of basic calcium phosphate from amorphous calcium phosphate. ENPP1 polypeptides have been shown to be effective in treating certain diseases of ectopic tissue calcification. ENPP1-Fc has been shown to reduce generalized arterial calcifications in a mouse model for GACI (generalized arterial calcification of infants), which is a severe disease occurring in infants and involving extensive arterial calcification (Albright, et al., 2015, Nature Comm.10006). Fusion proteins of ENPP1 also have been described to treat diseases of severe tissue calcification (see, e.g., PCT Application Publication Nos. WO 2014 / 126965 and WO 2016 / 187408), and a fusion protein of ENPP1 comprising a negatively charged bone-targeting domain has been described to treat GACI (PCT Application Publication Nos. WO 2011 / 113027 and WO 2012 / 125182). Currently no clinically approved treatments exist for these ultra-rare genetic, chronic, progressive, and life-threatening diseases in which patients especially children and infants who experience devastating effects on multiple systems of the body, leading to life-threatening or debilitating complications. ENPP1 Deficiency causes hypopyrophosphatemia and hypoadenosinemia, which, in turn, lead to pathological (especially arterial) calcification, which when it occurs in infants, is described in literature as Generalized Arterial Calcification of Infancy (GACI). Infants with ENPP1 Deficiency have high mortality, particularly in the first 0 to 6 months of life. No targeted therapy exists for this disease, thus, ENPP1 Deficiency has a high unmet medical need. SUMMARY The disclosure relates to administration of an ENPP1 agent to an infant at a dose of about 2.4 mg per kilogram of body weight of the infant. In one aspect, the disclosure relates to administering to an infant having an ENPP1 deficiency or to an infant having an ABCC6 deficiency, an ENPP1 agent at a dose of about 2.4 mg per kilogram of the infant in order to restore a physiological level of ENPP1 protein and / or activity in the plasma or tissues of the infant. A physiological level of ENPP1 activity in the Atty. Docket No.4427-12602 plasma or tissues, as used herein, is an amount or concentration of ENPP1 polypeptide sufficient to achieve and maintain a physiological level of PPi in human serum. In another aspect, the disclosure relates to administering to an infant having an ENPP1 deficiency or to an infant having an ABCC6 deficiency, an ENPP1 agent at a dose of about 2.4 mg per kilogram of the infant in order to restore a physiological level of Pi and / or PPi in the plasma of the infant The physiological level of Pi and PPi in human plasma (and in mammals generally) is 1-3 mM and 1-3 µM respectively. The median levels of PPi in healthy human subject is about 2 µM. In another aspect, the disclosure relates to a method for preventing progression of or reducing vascular calcification in an infant with ENPP1 Deficiency or in an infant having an ABCC6 deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce vascular calcification in the infant. In another aspect, the disclosure relates to a method for preventing the progression of or reducing pathological calcification in an infant with ENPP1 Deficiency or in an infant having an ABCC6 deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce pathological calcification in the infant. In another aspect, the disclosure relates to a method for preventing the progression of or reducing tissue calcification in an infant with ENPP1 Deficiency or an infant having an ABCC6 deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce tissue calcification in the infant. In another aspect, the disclosure relates to a method for increasing circulating pyrophosphate (PPi) in an infant with ENPP1 Deficiency or in an infant having an ABCC6 deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby increase circulating PPi in the infant. In another aspect, the disclosure relates to a method for ameliorating one or more symptoms of ENPP1 Deficiency in an infant or one or more symptoms of ABCC6 deficiency in an infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby ameliorate one or more symptoms of ENPP1 Deficiency or one or more symptoms of ABCC6 Deficiency in the infant. In another aspect, the disclosure relates to a method for treating an infant with ENPP1 Deficiency or an infant having an ABCC6 deficiency, the method comprising: administering to Atty. Docket No.4427-12602 the infant an ENPP1 agent at a dose of about 2.4mg per kilogram of bodyweight of the infant to thereby treat the infant. In yet another aspect, the disclosure relates to a method for treating an infant with ENPP1 Deficiency or an infant with ABCC6 deficiency, the method comprising administering to the infant an ENPP1 agent in an amount effective to treat, or otherwise ameliorate one or more symptoms associated with, the infant’s ENPP1 deficiency or the infant’s ABCC6 deficiency. In yet another aspect, the disclosure relates to a method for preventing the progression of or reducing pathological calcification in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce pathological calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of an age greater than 30 minutes and less than 12 months. In yet another aspect, the disclosure relates to a method for preventing the progression of or reducing pathological ossification in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce tissue calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In yet another aspect, the disclosure relates to a method for increasing circulating pyrophosphate (PPi) in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby increase circulating PPi in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In yet another aspect, the disclosure relates to a method for preventing the progression of or reducing pathological calcification in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby prevent the progression of or reduce pathological calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In yet another aspect, the disclosure relates to a method for preventing the progression of or reducing pathological ossification in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby prevent the progression of or reduce pathological ossification in the infant, wherein said infant is under the age of 1 year or wherein an infant is of age greater than 30 minutes and less than 12 months. In yet another aspect, the disclosure relates to a method for increasing circulating pyrophosphate (PPi) in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the Atty. Docket No.4427-12602 method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby increase circulating PPi in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 2.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.6 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. Atty. Docket No.4427-12602 In another aspect, the disclosure relates to a syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In some embodiments of any of the aforesaid syringes, the pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20. In some embodiments of any of the aforesaid syringes, the pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70 mM sucrose, about 32 mM (D) mannitol, and about 0.02% w / v polysorbate 20. In some embodiments of any of the aforesaid syringes, the pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70.1 mM sucrose, about 32.9 mM (D) mannitol, and about 0.02% w / v polysorbate 20. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount ranging from 1-200 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 200 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 175 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 150 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. Atty. Docket No.4427-12602 In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 125 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 100 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 75 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 50 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 25 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 10 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 5 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. Atty. Docket No.4427-12602 In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 4 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 3 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 2 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In some embodiments of any of the aforesaid vials, the ENPP1 polypeptide in the vial at a concentration of 1-200 mg / ml is further diluted to achieve a therapeutic dose of ENPP1 polypeptide for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months, and wherein the therapeutic dose is selected from the group consisting of 2.4 mg / kg, 1.8 mg / kg, 1.2 mg / kg, 0.8 mg / kg, 0.6 mg / kg, and 0.2 mg / kg of body weight of the infant having pathological calcification. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount ranging from 0.2 mg to 2.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 2.4 mg per kilogram of body weight of an infant having pathological calcification and Atty. Docket No.4427-12602 wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.6 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In another aspect, the disclosure relates to a vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months. In some embodiments of any of the aforesaid vials, the pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20. Atty. Docket No.4427-12602 In some embodiments of any of the aforesaid vials, the pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70 mM sucrose, about 32 mM (D) mannitol, and about 0.02% w / v polysorbate 20. In some embodiments of any of the aforesaid vials, the pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70.1 mM sucrose, about 32.9 mM (D) mannitol, and about 0.02% w / v polysorbate 20. In some embodiments of any of the aforesaid vials or syringes, the pathological calcification in the infant is caused by ENPP1 deficiency. In some embodiments of any of the aforesaid vials or syringes, pathological calcification in the infant is caused by ABBC6 deficiency. In some embodiments of any of the aforesaid vials or syringes, pathological calcification in the infant is caused by General arterial calcification of infancy (GACI). In some embodiments of any of the aforesaid vials or syringes, pathological calcification in the infant is caused by Pseudoxanthoma Elasticum (PXE). In some embodiments of any of the aforesaid vials or syringes, pathological calcification in the infant is caused by calciphylaxis. In some embodiments of any of the aforesaid vials or syringes, the administration to infant is by subcutaneous injection. In some embodiments, the disclosure relates to methods in which the administered dose is 2.4 (± 1-10 %) mg per kilogram of the infant. For example, the dose can be 2.64 mg / kg (2.4 +10% mg / kg), or 2.16 mg / kg (2.4-10% mg / kg), or 2.52 mg / kg (2.4 + 5% mg / kg), or 2.28 mg / kg (2.4-5% mg / kg) or 2.424 mg / kg (2.4 + 1% mg / kg) or 2.376 mg / kg (2.4 -1% mg / kg) of the infant. In some embodiments, the disclosure relates to methods in which the total administered dose is 2.4 mg of ENPP1 polypeptide per kg of the infant. For example, the infant can be administered 1.2 mg / kg of ENPP1 polypeptide twice a week leading to a total administered dose of 2.4 mg of ENPP1 polypeptide per kg of the infant. In some embodiments, the infant can be administered 0.8 mg / kg of ENPP1 polypeptide three times a week leading to a total administered dose of 2.4 mg of ENPP1 polypeptide per kg of the infant. In some embodiments, the infant can be administered 0.6 mg / kg of ENPP1 polypeptide four times a week leading to a total administered dose of 2.4 mg of ENPP1 polypeptide per kg of the infant. In some embodiments, the infant can be administered 0.4 mg / kg of ENPP1 polypeptide six times a week leading to a total administered dose of 2.4 mg of ENPP1 polypeptide per kg of the infant. Atty. Docket No.4427-12602 In some embodiments of the methods described herein, the infant is administered a dose of 2.4 mg of the polypeptide per kilogram of body weight, wherein the 2.4 mg / kg dose is provided in a syringe. In some embodiments of the methods described herein, the infant is administered a dose of 2.4 mg of the ENPP1 polypeptide per kilogram of body weight, wherein the 2.4 mg / kg dose is provided in a vial for administration. In some embodiments of any of the methods described herein, the infant can be, e.g., one who has discontinued (e.g., at least 14 days prior to treatment with the ENPP1 agent) treatment with (or is otherwise not receiving at the time of treatment with the ENPP1 agent) one or more (or all) of the following: a bisphosphonate, an anti-FGF23 antibody or FGF23 antagonist, a calcimimetic, an antacid, a corticosteroid, or a PTH suppressor. In some embodiments of any of the methods described herein, the infant is one who has been pre-treated with one or more statins and / or one or more proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors. Preferably, such pre-treatment include consistent dosage and frequency of the one or more statins and / or one or more PCSK9 inhibitors for 3 or more years prior to treatment according to methods described herein. In some embodiments of any of the methods described herein, the infant has not been diagnosed with a malignancy prior to treatment according to methods described herein, with the exception of non-melanoma skin cancers and / or cervical carcinoma in situ. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least one time per week or once weekly. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least two times per week. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least three times per week. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least four times per week. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least five times per week. In some embodiments of any of the methods described herein, the ENPP1 agent is administered at least six times per week. In some embodiments of any of the methods described herein, the ENPP1 agent is administered once every two weeks. Atty. Docket No.4427-12602 In some embodiments of any of the methods described herein, the ENPP1 agent is administered once every three weeks. In some embodiments of any of the methods described herein, the ENPP1 agent is administered once every month. In some embodiments of any of the methods described herein, the ENPP1 agent is administered to the infant at least two times per week following an initial dose. In some embodiments of any of the methods described herein, the ENPP1 agent is administered subcutaneously. In some embodiments of any of the methods described herein, the ENPP1 agent is administered by a caregiver. In some embodiments of any of the methods described herein, the ENPP1 agent is administered under a dosing regimen comprising: (a) an initial dose of about 2.4 mg per kilogram of the infant. In some embodiments of any of the methods described herein, the initial dose of the ENPP1 agent and the maintenance dose of the ENPP1 agent are the same amount. In some embodiments of any of the methods described herein, the administered ENPP1 agent comprises the catalytic domain of ENPP1. In some embodiments of any of the methods described herein, the administered ENPP1 agent comprises the nuclease domain of ENPP1. In some embodiments of any of the methods described herein, the administered ENPP1 agent comprises the extracellular domain of ENPP1. In some embodiments of any of the methods described herein, the administered ENPP1 agent comprises the catalytic and nuclease domains of ENPP1. In some embodiments of any of the methods described herein, the administered ENPP1 agent comprises a heterologous moiety; the heterologous moiety may be a polypeptide. In some embodiments of any of the methods described herein, the heterologous moiety increases the circulating half-life of the ENPP1 agent relative to the circulating half-life of the ENPP1 agent lacking the heterologous moiety. In some embodiments of any of the methods described herein, the heterologous moiety comprises the Fc region of an immunoglobulin molecule; the immunoglobulin molecules may be a human immunoglobulin molecule; the immunoglobulin molecule may be an IgG1. Atty. Docket No.4427-12602 In some embodiments of any of the methods described herein, the heterologous moiety comprises albumin; the heterologous moiety comprises serum albumin; the heterologous moiety comprises human serum albumin. In some embodiments of any of the methods described herein, the ENPP1 agent comprising amino acid residues 99 (PSCAKE) to 925(QED) of SEQ ID NO:1. In some embodiments of any of the methods described herein, the ENPP1 agent comprising amino acid residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:3. In some embodiments of any of the methods described herein, the ENPP1 agent comprising the amino acid sequence depicted in SEQ ID NO:2. In some embodiments of any of the methods described herein, the ENPP1 agent comprising the amino acid sequence depicted in SEQ ID NO:3. In some embodiments of any of the methods described herein, the ENPP1 agent comprising the amino acid sequence depicted in SEQ ID NO:4. In some embodiments of any of the methods described herein, the ENPP1 agent comprising the amino acid sequence depicted in SEQ ID NO:5. In some embodiments of any of the methods described herein, the infant has or is suspected of having generalized arterial calcification of infancy (GACI). In some embodiments of any of the methods described herein, the infant has or is suspected of having autosomal recessive hypophosphatemic rickets type 2 (ARHR2). In some embodiments of any of the methods described herein, the infant has or is suspected of having Pseudoxanthoma elasticum (PXE). In some embodiments of any of the methods described herein, the infant having ABCC6 deficiency and exhibits symptoms similar to an infant having autosomal recessive hypophosphatemic rickets type 2 (ARHR2) or generalized arterial calcification of infancy (GACI). In some embodiments of any of the methods described herein, the ENPP1 agent is administered under a dosing regimen comprising: (a) an initial dose of about 2.4 mg per kilogram of the infant and (b) about seven days after the initial dose, twice weekly administration of maintenance doses of the ENPP1 agent of about 2.4 mg per kilogram of bodyweight of the infant. In some embodiments of any of the methods described herein, the infant has or is suspected of having one or more of kidney and bladder stones, dental pulp stones, gall stones, Atty. Docket No.4427-12602 salivary gland stones, chronic calculous prostatitis, testicular microliths, calcification in hemodialysis patients, atherosclerosis, malacoplakia, scleroderma (systemic sclerosis), ARHR2, calcinosis cutis, calcific aortic stenosis, calcific tendonitis, synovitis and arthritis, diffuse interstitial skeletal hyperostosis, juvenile dermatomyositis, Generalized Arterial Calcification of Infancy (GACI), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, calcification of atherosclerotic plaques, Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), Pseudoxanthoma elasticum (PXE), ankylosing spondylitis, hardening of the arteries, calciphylaxis, and systemic lupus erythematosus. In some embodiments of any of the methods described herein, the infant is characterized by one or more of the inclusion criteria described herein. For example, an infant described herein can have a plasma PPi concentration of below approximately 1000nM, e.g., prior to treatment with an ENPP1 agent. In some embodiments, the infant is not characterized by any of the exclusion criteria described herein. For example, the infant can be one who does not have advanced eye disease prior to, or during, treatment with an ENPP1 agent. In some embodiments, the infant does not have advanced eye disease requiring anti-VEGF treatment (for example) prior to, or during, treatment with an ENPP1 agent. In some embodiments of any of the methods described herein, the infant exhibits no adverse events post administration of said dose. In some embodiments of any of the methods described herein, the infant exhibits low levels of anti-drug antibody (ADA) post administration of said dose. In some embodiments of any of the methods described herein, the infant exhibits no adverse effects post administration of said dose. In some embodiments of any of the methods described herein, the infant post administration of said dose exhibits PPi levels that are either equal or greater than the PPi levels of a healthy individual. In some embodiments of any of the methods described herein, the infant is under the age of 12 months. In some embodiments of any of the methods described herein, the infant is of an age that is greater than 30 minutes but less than 12 months. In some embodiments of any of the methods described herein, the infant is 1 day old, 3 days old, 5 days old, 1 week old, 2 weeks old, 3 weeks old, 1 month old, 2 months old, 3 months Atty. Docket No.4427-12602 old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, or 11 months old. In some embodiments of any of the methods described herein, the infant is 1-7 days old, 7-14 days old, 14-21 days old, 21-28 days old, 28-35 days old, 35-42 days old, 42-49 days old, 49-56 days old, 56-63 days old, 63+70 days old, 70-77 days old, 77-84 days old, 84-91 days old, 91-98 days old, 98-105 days old, 105-112 days old, 112-119 days old, 119-126 days old, 126- 133 days old, 133-140 days old, 140-147 days old, 147-154 days old, 154-161 days old, 161-168 days old, 175-182 days old, 182-189 days old, 196-203 days old, 203-210 days old, 210-217 days old, 217-224 days old, 224-231 days old, 231-238 days old, 238-245 days old, 245-252 days old, 252-259 days old, 259-266 days old, 266-273 days old, 273-280 days old, 280-287 days old, 287-294 days old, 294-301 days old, 301-308 days old, 308-315 days old, 315 -322 days old, 322-329 days old, 329-336 days old, 336-343 days old, 343-350 days old, 350-357 days old, or 357-364 days old. In some embodiments of any of the methods described herein, the infant is not an adult. In some embodiments of any of the methods described herein, the infant is not a child over the age of 1. DESCRIPTION BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Figure 1 presents a schematic overview of ENPP1 Deficiency. Figure 2 shows the full, unprocessed amino acid sequence of wild-type ENPP1 precursor protein (SEQ ID NO: 1). The cytosolic and transmembrane regions are underlined. Potential N- glycosylation sites are in bold. PSCAKE (residues 99-104; boxed) is the start of soluble ENPP1 protein portion which includes SMB1 (residues 104-144) and SMB2 (residues 145-189). Figure 3 illustrates certain domains of human ENPP1 such as cytosolic domain, transmembrane domain, SMB domain, catalytic domain and nuclease domain. Figure 4 shows the amino acid sequence of a soluble wild-type ENPP1 polypeptide (SEQ ID NO: 2). Figure 5A and Figure 5B show a multiple sequence alignment of various vertebrate soluble ENPP1 polypeptides and human soluble ENPP1 polypeptide (SEQ ID NOs: 1 and 7-10). The various soluble ENPP1 polypeptides correspond to the following species and represent Atty. Docket No.4427-12602 regions of the specific NCBI accession number: Mouse (NCBI accession NP_001295256.1; SEQ ID NO:7), Cow (NCBI accession NP_001193141; SEQ ID NO: 8), Rabbit (NCBI accession NP_001162404.1; SEQ ID NO:9), Human (NCBI accession NP_006199.2; SEQ ID NO: 1), and Baboon (NCBI accession NP_001076211.2; SEQ ID NO: 10). Figure 6 presents a schematic overview of ABCC6 Deficiency. Figure 7 shows the increase of plasma pyrophosphate (PPi) in a 3 month old infant subject post administration of 2.4 mg / kg of ENPP1 polypeptide (INZ-701). Figure 8 shows the increase of plasma pyrophosphate (PPi) in a 2 month old infant subject post administration of 2.4 mg / kg of ENPP1 polypeptide (INZ-701). Figure 9 shows non-contrast CT scan indicating complete resolution of arterial calcification in an infant dosed with 2.4 mg / kg of ENPP1 polypeptide (INZ-701). DEFINITIONS The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below or elsewhere in the specification, to provide additional guidance to the practitioner in describing the compositions and methods of the disclosure and how to make and use them. The scope or meaning of any use of a term will be apparent from the specific context in which the term is used. An “ENPP1 Deficiency” is characterized by a reduced level of ENPP1 enzymatic activity in serum or plasma of a subject. ENPP1 Deficiency is a rare, genetic disorder caused by inactivating mutations in the ENPP1 gene that encodes the ENPP1 enzyme. ENPP1 is an integral transmembrane protein whose extracellular domains carry pyrophosphatase and phosphodiesterase activities. ENPP1 converts extracellular ATP to inorganic pyrophosphate (PPi) and AMP. ENPP1 deficiency is an ultra-rare genetic disorder with an incidence of 1 in 64,000 pregnancies. ENPP1 Deficiency causes hypopyrophosphatemia and hypoadenosinemia which, in turn, leads to ectopic (especially arterial) calcification (described in literature as Generalized Arterial Calcification of Infancy [GACI]), skeletal dysfunction secondary to rickets and osteomalacia (described in literature as Autosomal Recessive Hypophosphatemic Rickets 2 [ARHR2]) and occlusive neo-intimal proliferation. Beyond symptomatic and palliative interventions, no targeted therapy exists for this disease. Thus, ENPP1 Deficiency has a high unmet medical need. Infants with ENPP1 Deficiency have high mortality in the first 0 to 12 months of life of an infant , children of ages 1-12 and adults with ENPP1 Deficiency experience ongoing risk for organ calcification and dysfunction, debilitating rickets that progresses to osteomalacia in adulthood with severe bone and joint pain, fatigue, muscle weakness, and repeated bone fractures, all Atty. Docket No.4427-12602 symptoms that lead to poor quality of life and function. Hypopyrophosphatemia causes a reactive increase in fibroblast growth factor 23 (FGF23) leading to hyperphosphaturia (the ENPP1 Deficiency “biochemical axis”), an essential feature in the pathophysiology of ENPP1 Deficiency. ENPP1 Deficiency is characterized biochemically by low plasma PPi levels and clinically characterized by vascular calcification in infants (GACI Type phenotype) and rickets (ARHR2 phenotype) post-infancy and intimal proliferation. GACI (generalized arterial calcification of infants) is a severe disease occurring in infants and involving extensive arterial calcification (Albright, et al., 2015, Nature Comm.10006). Reduced ENPP1 enzymatic activity may occur via a reduction in the amount of ENPP1 enzyme present in serum or plasma of a subject relative to the amount of ENPP1 enzyme present in serum or plasma of a normal subject, and / or a reduction in the level of enzymatic activity of ENPP1 detected in serum or plasma of a subject relative to the level of enzymatic activity of ENPP1 detected in a normal subject, and / or via a defect in expression of ENPP1 gene at the transcriptional (RNA and / or mRNA) or translational levels, for example via a defect in the ENPP1 gene or a control element affecting ENPP1 gene expression, relative to normal expression the ENPP1 gene in a subject. ENPP1 enzymatic activity is defined below. “Enzymatically active” with respect to an ENPP1 polypeptide, or, as used herein, “enzymatic activity” with respect to an ENPP1 polypeptide, is defined as possessing ATP hydrolytic activity into AMP and PPi and / or AP3a hydrolysis to ATP. NPP1 readily hydrolyze ATP into AMP and PPi. The steady-state Michaelis-Menten enzymatic constants of NPP1 are determined using ATP as a substrate. NPP1 can be demonstrated to cleave ATP by HPLC analysis of the enzymatic reaction, and the identity of the substrates and products of the reaction are confirmed by using ATP, AMP, and ADP standards. The ATP substrate degrades over time in the presence of NPP1, with the accumulation of the enzymatic product AMP. Using varying concentrations of ATP substrate, the initial rate velocities for NPP1 are derived in the presence of ATP, and the data is fit to a curve to derive the enzymatic rate constants. At physiologic pH, the kinetic rate constants of NPP1 are Km=144 µM and kcat=7.8 s-1. As used herein the term “plasma pyrophosphate (PPi) levels” refers to the amount of pyrophosphate present in plasma of animals. In certain embodiments, animals include rat, mouse, cat, dog, human, cow and horse. It is necessary to measure PPi in the plasma rather than serum because of release from platelets. There are several ways to measure PPi, one of which is by enzymatic assay using uridine-diphosphoglucose (UDPG) pyrophosphorylase (Lust & Seegmiller, 1976, Clin. Chim. Acta 66:241-249; Cheung & Suhadolnik, 1977, Anal. Biochem. 83:61-63) with modifications. Typically, plasma PPi levels in healthy human subjects range from about 1µm to about 3 µM, in some cases between 1-2 µm. A normal level of ENPP1 in plasma refers to the amount of Atty. Docket No.4427-12602 ENPP1 protein required to maintain a normal level of plasma pyrophosphate (PPi) in a healthy subject. A normal level of PPi in healthy humans corresponds to 1-3 µM. Subjects who have a deficiency of ENPP1 exhibit low PPi levels which range from at least 10% below normal levels, at least 20% below normal levels, at least 30% below normal levels, at least 40% below normal levels, at least 50% below normal levels, at least 60% below normal levels, at least 70% below normal levels, at least 80% below normal levels and combinations thereof. In patients afflicted with GACI, the PPi levels are found to be less than 1 µm and in some cases are below a detectable level. In patients afflicted with ENPP1 deficiency, the PPi levels are found to be less than 1 µm, such as 967 nm or 0.967 µm . In patients afflicted with PXE, the PPi levels are below 500 nm or 0.5 µm. (Arterioscler Thromb Vasc Biol.2014 Sep;34(9):1985-9; Braddock et al., Nat Commun.2015; 6: 10006.) An “ABCC6 Deficiency” may be indicated in a number of ways, for example, by a reduced expression levels of ABCC6 enzyme in a subject. Subjects having ABCC6 deficiency can be identified by the presence of one or more physiological symptoms such as ocular calcification, skin calcification yellow papules, angioid streaks, visual impairment, calcification of soft connective tissues including the cardiovascular system, and / or, the presence of ABCC6 mutations that affect the activity and expression of ABCC6 protein. Details on diagnosis and classification of ABCC6 mutations are known in art. (Expert Opin Orphan Drugs.2014 Jun 1; 2(6): 567–577). ABCC6 deficiency may result in PXE. Reduced ABCC6 enzymatic activity may occur via a reduction in the amount of ABCC6 enzyme present in a subject relative to the amount of ABCC6 enzyme present in a normal subject, and / or a reduction in the level of enzymatic activity of ABCC6 in a subject relative to the level of enzymatic activity of ABCC6 detected in a normal subject, and / or via a defect in expression of ABCC6 gene at the transcriptional (RNA and / or mRNA) or translational levels, for example via a defect in the ABCC6 gene or a control element affecting ABCC6 gene expression, relative to normal expression the ABCC6 gene in a subject. A subject with ABCC6 deficiency can be identified by screening for ABCC6 gene mutations. Several methods for detecting gene mutations are known in art. For instance, detection of mutation in ABCC6 genes can performed by following the protocols described in J Med Genet.2007 Oct; 44(10): 621–628. (Mutation detection in the ABCC6 gene and genotype– phenotype analysis in a large international case series affected by pseudoxanthoma elasticum, Ellen G Pfendner, et al) “ABCC6 deficient patient” or “ABCC6 deficient subject” or “ABCC6 deficient infant” as used herein, refers to a patient having at least one pathogenic mutation in the ABCC6 gene that affects activity and / or expression of ABC66 protein. “Pathological calcification”: As used herein, the term refers to the abnormal deposition of calcium salts in soft tissues, secretory and excretory passages of the body causing it to harden. There are two types, dystrophic calcification which occurs in dying and dead tissue and Atty. Docket No.4427-12602 metastatic calcification which elevated extracellular levels of calcium (hypercalcemia), exceeding the homeostatic capacity of cells and tissues. Calcification can involve cells as well as extracellular matrix components such as collagen in basement membranes and elastic fibers in arterial walls. Some examples of tissues prone to calcification include: Gastric mucosa – the inner epithelial lining of the stomach, Kidneys and lungs, Cornea, Systemic arteries and Pulmonary veins. “Pathological ossification”: As used herein, the term refers to a pathological condition in which bone arises in tissues not in the osseous system and in connective tissues usually not manifesting osteogenic properties. Ossification is classified into three types depending on the nature of the tissue or organ being affected, endochondral ossification is ossification that occurs in and replaces cartilage. Intramembranous ossification is ossification of bone that occurs in and replaces connective tissue. Metaplastic ossification the development of bony substance in normally soft body structures; called also heterotrophic ossification. A “deficiency” of NPP1 refers to a condition in which the subject has less than or equal to 5%-10% of normal levels of NPP1 in blood plasma. Normal levels of NPP1in healthy human subjects is approximately between 10 to 30 ng / ml. (Am J Pathol.2001 Feb; 158(2): 543–554.) A “deficiency” of ABCC6 refers to a condition in which the subject has less than or equal to 5%-10% of normal levels of ABCC6 expression. ABCC6 protein is expressed in liver and levels of ABCC6 protein can be measured by means of liver biopsy. A “low” level of PPi refers to a condition in which the subject has less than or equal to 2%-5% of normal levels of plasma pyrophosphate (PPi). Normal levels of Plasma PPi in healthy human subjects is approximately 1-3 µm. (Khursigara G, Huertas P, Wenkert D, O'Brien K, Sabbagh Y. Effects of food, fasting, and exercise on plasma pyrophosphate levels and ENPP1 activity in healthy adults. Bone.2023 Jun;171:116750). “Ectopic calcification” refers to a condition characterized by a pathologic deposition of calcium salts in tissues or bone growth in soft tissues. “Ectopic calcification of soft tissue” refers to inappropriate biomineralization, typically composed of calcium phosphate, hydroxyapatite, calcium oxalates and octacalcium phosphates occurring in soft tissues leading to loss of hardening of soft tissues. “Arterial calcification” refers to ectopic calcification that occurs in arteries and heart valves leading to hardening and or narrowing of arteries. Calcification in arteries is correlated with atherosclerotic plaque burden and increased risk of myocardial infarction, increased ischemic episodes in peripheral vascular disease, and increased risk of dissection following angioplasty. Atty. Docket No.4427-12602 “Venous calcification” refers to ectopic calcification that occurs in veins that reduces the elasticity of the veins and restricts blood flow which can then lead to increase in blood pressure and coronary defects. “Vascular calcification” refers to the pathological deposition of mineral in the vascular system. It has a variety of forms, including intimal calcification and medial calcification, but can also be found in the valves of the heart. Vascular calcification is associated with atherosclerosis, diabetes, certain heredity conditions, and kidney disease, especially CKD. Patients with vascular calcification are at higher risk for adverse cardiovascular events. Vascular calcification affects a wide variety of patients. Idiopathic infantile arterial calcification is a rare form of vascular calcification where the arteries of neonates calcify. “Brain calcification” (BC) refers to a nonspecific neuropathology wherein deposition of calcium and other mineral in blood vessel walls and tissue parenchyma occurs leading to neuronal death and gliosis. Brain calcification is” often associated with various chronic and acute brain disorders including Down’s syndrome, Lewy body disease, Alzheimer’s disease, Parkinson’s disease, vascular dementia, brain tumors, and various endocrinologic conditions. Calcification of heart tissue refers to accumulation of deposits of calcium (possibly including other minerals) in tissues of the heart, such as aorta tissue and coronary tissue. “Chronic kidney disease (CKD)” As used herein, the term refers to abnormalities of kidney structure or function that persist for more than three months with implications for health. Generally excretory, endocrine and metabolic functions decline together in most chronic kidney diseases. Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD) and vascular calcification is one of the strongest predictors of cardiovascular risk. With decreasing kidney function, the prevalence of vascular calcification increases, and calcification occurs years earlier in CKD patients than in the general population. Preventing, reducing and / or reversing vascular calcification may result in increased survival in patients with CKD. Clinical symptoms of chronic kidney diseases include itching, muscle cramps, nausea, lack of appetite, swelling of feet and ankles, sleeplessness and labored breathing. Chronic kidney disease if left untreated tends to progress into End stage renal disease (ESRD). Common symptoms of ESRD include an inability to urinate, fatigue, malaise, weight loss, bone pain, changes in skin color, a frequent formation of bruises, and edema of outer extremities like fingers, toes, hands and legs. Calciphylaxis or calcific uremic arteriolopathy (CUA) is a condition that causes calcium to build up inside the blood vessels of the fat and skin. A subpopulation of patients suffering from ESRD can also develop Calciphylaxis. Common symptoms of Calciphylaxis include large purple net-like patterns on skin, deep and painful lumps that ulcerate creating open sores with black-brown crust that fails to heal, skin lesions on the lower limbs or areas with higher fat content, such as thighs, breasts, buttocks, and abdomen. A Atty. Docket No.4427-12602 person with calciphylaxis may have higher than normal levels of calcium (hypercalcemia) and phosphate (hyperphosphatemia) in the blood. They may also have symptoms of hyperparathyroidism. Hyperparathyroidism occurs when the parathyroid glands make excess parathyroid hormone (PTH). Reduced plasma pyrophosphate (PPi) levels are also present in vascular calcification associated with end stage renal disease (ESRD). Vascular calcifications associated with ESRD contributes to poor outcomes by increasing pulse pressure, causing or exacerbating hypertension, and inducing or intensifying myocardial infarctions and strokes. Most patients with ESRD do not die of renal failure, but from the cardiovascular complications of ESRD, and it is important to note that many very young patients with ESRD on dialysis possess coronary artery calcifications. The histologic subtype of vascular calcification associated with CKD is known as Mönckeburg’s sclerosis, which is a form of vessel hardening in which calcium deposits are found in the muscular layers of the medial vascular wall. This form of calcification is histologically distinct from intimal or neo-intimal vascular wall calcification commonly observed in atherosclerosis but identical to the vascular calcifications observed in human CKD patients, and in the rodent models of the disease described herein. “Generalized arterial calcification of infants (GACI)” (also known as IACI)”, as used herein, refers to a disorder affecting the circulatory system that becomes apparent before birth or within the first few months of life. It is characterized by abnormal accumulation of the mineral calcium (calcification) in the walls of the blood vessels that carry blood from the heart to the rest of the body (the arteries). Calcification often occurs along with thickening of the lining of the arterial walls (the intima). These changes lead to narrowing (stenosis) and stiffness of the arteries, which forces the heart to work harder to pump blood. As a result, heart failure may develop in affected individuals, with signs and symptoms including difficulty breathing, accumulation of fluid (edema) in the extremities, a bluish appearance of the skin or lips (cyanosis), severe high blood pressure (hypertension), and an enlarged heart (cardiomegaly). People with GACI may also have calcification in other organs and tissues, particularly around the joints. In addition, they may have hearing loss or softening and weakening of the bones referred to as rickets. General arterial calcification (GACI) or Idiopathic Infantile Arterial Calcification (IIAC) characterized by abnormal accumulation of the mineral calcium (calcification) in the walls of the blood vessels that carry blood from the heart to the rest of the body (the arteries). The calcification often occurs along with thickening of the lining of the arterial walls (the intima). These changes lead to narrowing (stenosis) and stiffness of the arteries, which forces the heart to work harder to pump blood. As a result, heart failure may develop in affected individuals, with signs and symptoms including difficulty breathing, accumulation of fluid (edema) in the extremities, a bluish appearance of the skin or lips (cyanosis), severe high blood pressure (hypertension), and an enlarged heart (cardiomegaly). Atty. Docket No.4427-12602 The term “Infant” as used herein refers to a human in his or her first year of life. Typically, infantile stage refers to the age from birth to under the age of 1 year. Under the age of 1 year is equal to under the age of 12 months. Thus, an infant as used herein refers to an age inclusive of the first hours and the first day of life up of the newborn to the age of 11 months but does not include 12 months of age. The term “children” as used herein refers to a human child and refers to a life stage of having an age between greater than one year but less than 13 years of age. (i.e. between the ages of 1-12). “Arterial calcification” or “Vascular calcification” or “hardening of arteries”, As used herein, the term refers to a process characterized by thickening and loss of elasticity of muscular arteries walls. The thickening and loss of elasticity occurs in two distinct sites, the intimal and medial layers of the vasculatures (Medial vascular calcification). Intimal calcification is associated with atherosclerotic plaques and medial calcification is characterized by vascular stiffening and arteriosclerosis. This results in a reduction of arterial elasticity and an increased propensity for morbidity and mortality due to the impairment of the cardiovascular system’s hemodynamics. “Mineral bone disorders (MBD)”, as used herein, the term refers to a disorder characterized by abnormal hormone levels cause calcium and phosphorus levels in a person’s blood to be out of balance. Mineral and bone disorder commonly occurs in people with CKD and affects most people with kidney failure receiving dialysis. Osteopenia is a bone condition characterized by decreased bone density, which leads to bone weakening and an increased risk of bone fracture. Osteomalacia is a bone disorder characterized by decreased mineralization of newly formed bone. Osteomalacia is caused by severe vitamin D deficiency (which can be nutritional or caused by a hereditary syndrome) and by conditions that cause very low blood phosphate levels. Both osteomalacia and osteopenia increase the risk of breaking a bone. Symptoms of osteomalacia include bone pain and muscle weakness, bone tenderness, difficulty walking, and muscle spasms. “Age related osteopenia”, as used herein refers to a condition in which bone mineral density is lower than normal. Generally, patients with osteopenia have a bone mineral density T- score of between -1.0 and -2.5. Osteopenia if left untreated progresses into Osteoporosis where bones become brittle and are extremely prone to fracture. “Ossification of posterior longitudinal ligament (OPLL)”, as used herein, the term refers to a hyperostotic (excessive bone growth) condition that results in ectopic calcification of the posterior longitudinal ligament. The posterior longitudinal ligament connects and stabilizes the bones of the spinal column. The thickened or calcified ligament may compress the spinal cord, producing myelopathy. Symptoms of myelopathy include difficulty walking and difficulty with Atty. Docket No.4427-12602 bowel and bladder control. OPLL may also cause radiculopathy, or compression of a nerve root. Symptoms of cervical radiculopathy include pain, tingling, or numbness in the neck, shoulder, arm, or hand. Clinical symptoms and signs caused by OPLL are categorized as: (1) myelopathy, or a spinal cord lesion with motor and sensory disturbance of the upper and lower limbs, spasticity, and bladder dysfunction; (2) cervical radiculopathy, with pain and sensory disturbance of the upper limbs; and (3) axial discomfort, with pain and stiffness around the neck. The most common symptoms in the early stages of OPLL include dysesthesia and tingling sensation in hands, and clumsiness. With the progression of neurologic deficits, lower extremity symptoms, such as gait disturbance may appear. OPLL is detected on lateral plain radiographs, and the diagnosis and morphological details of cervical OPLL have been clearly demonstrated by magnetic resonance imaging (MRI) and computed tomography (CT). “Pseudoxanthoma elasticum (PXE)”, as used herein, the term refers a progressive disorder that is characterized by the accumulation of deposits of calcium and other minerals (mineralization) in elastic fibers. Elastic fibers are a component of connective tissue, which provides strength and flexibility to structures throughout the body. In PXE, mineralization can affect elastic fibers in the skin, eyes, and blood vessels, and less frequently in other areas such as the digestive tract. People with PXE may have yellowish bumps called papules on their necks, underarms, and other areas of skin that touch when a joint bends. Mineralization of the blood vessels that carry blood from the heart to the rest of the body (arteries) may cause other signs and symptoms of PXE. For example, people with this condition can develop narrowing of the arteries (arteriosclerosis) or a condition called claudication that is characterized by cramping and pain during exercise due to decreased blood flow to the arms and legs. Pseudoxanthoma elasticum (PXE), also known as Grönblad–Strandberg syndrome, is a genetic disease that causes fragmentation and mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis. PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1). In some cases, a portion of infants survive GACI and end up developing Pseudoxanthoma elasticum (PXE) when they grow into adults. PXE is characterized by the accumulation of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue. Connective tissue provides strength and flexibility to structures throughout the body. Features characteristic of PXE that also occur in GACI include yellowish bumps called papules on the underarms and other areas of skin that touch when a joint bends (flexor areas); arterial stenosis, and abnormalities called angioid streaks affecting tissue at the back of the eye (retinal hemorrhage), which is detected during an eye examination. Atty. Docket No.4427-12602 “End stage renal disease (ESRD), as used herein, the term refers to an advanced stage of chronic kidney disease where kidneys of the patient are no longer functional. Common symptoms include fatigue associated with anemia (low blood iron), decreased appetite, nausea, vomiting, abnormal lab values including elevated potassium, abnormalities in hormones related to bone health, elevated phosphorus and / or decreased calcium, high blood pressure (hypertension), swelling in hands / legs / eyes / lower back (sacrum) and shortness of breath. “Calcific uremic arteriolopathy (CUA)” or “Calciphylaxis”, as used herein refers to a condition with high morbidity and mortality seen in patients with kidney disease, especially in those with end stage renal disease (ESRD). It is characterized by calcification of the small blood vessels located within the fatty tissue and deeper layers of the skin leading to blood clots, and the death of skin cells due to reduced blood flow caused by excessive calcification. “Hypophosphatemic rickets”, as used herein refers to a disorder in which the bones become soft and bend easily, due to low levels of phosphate in the blood. Symptoms usually begin in early childhood and can range in severity from bowing of the legs, bone deformities; bone pain; joint pain; poor bone growth; and short stature. “Hereditary Hypophosphatemic Rickets” as used herein refers to a disorder related to low levels of phosphate in the blood (hypophosphatemia). Phosphate is a mineral that is essential for the normal formation of bones and teeth. Most commonly, it is caused by a mutation in the PHEX gene. Other genes that can be responsible for the condition include the CLCN5, DMP1, ENPP1, FGF23, and SLC34A3 genes. Other signs and symptoms of hereditary hypophosphatemic rickets can include premature fusion of the skull bones (craniosynostosis) and dental abnormalities. The disorder may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy). In adults, hypophosphatemia is characterized by a softening of the bones known as osteomalacia. Another rare type of the disorder is known as hereditary hypophosphatemic rickets with hypercalciuria (HHRH) wherein in addition to hypophosphatemia, this condition is characterized by the excretion of high levels of calcium in the urine (hypercalciuria). “X-linked hypophosphatemia (XLH)”, as used herein, the term X-linked hypophosphatemia (XLH), also called X-linked dominant hypophosphatemic rickets, or X-linked Vitamin D-resistant rickets, is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. “Autosomal Recessive Hypophosphatemia Rickets type 2 (ARHR2)”, as used herein, the term refers to a hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and / or osteomalacia and slow growth. Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is caused by homozygous loss-of-function mutation in the ENPP1 gene. Atty. Docket No.4427-12602 “Autosomal Dominant Hypophosphatemic Rickets (ADHR)”, as used herein refers to a rare hereditary disease in which excessive loss of phosphate in the urine leads to poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR is characterized by impaired mineralization of bone, rickets and / or osteomalacia, suppressed levels of calcitriol (1, 25-dihydroxyvitamin D3), renal phosphate wasting, and low serum phosphate. Mutations in FGF23 render the protein more stable and uncleavable by proteases resulting in enhanced bioactivity of FGF23. The enhanced activity of FGF23 mutants reduce expression of sodium-phosphate co-transporters, NPT2a and NPT2c, on the apical surface of proximal renal tubule cells, resulting in renal phosphate wasting. Hypophosphatemic rickets (previously called vitamin D-resistant rickets) is a disorder in which the bones become painfully soft and bend easily, due to low levels of phosphate in the blood. Symptoms may include bowing of the legs and other bone deformities; bone pain; joint pain; poor bone growth; and short stature. In some affected babies, the space between the skull bones closes too soon leading to craniosynostosis. Most patients display Abnormality of calcium-phosphate metabolism, Abnormality of dental enamel, Delayed eruption of teeth and long, narrow head (Dolichocephaly). “Pre-treatment”, as used herein, means treatment prior to commencement of a treatment method described herein. “PCSK9 inhibitor” as used herein, the term refers to inhibitor that blocks the PCSK9 enzyme. Proprotein convertase subtilisin / kexin type 9 (PCSK9) is an enzyme that binds to low- density lipoprotein receptors (LDL receptors), which stops LDL being removed from the blood, leading to an increase in blood levels of LDL. The PCSK9 inhibitor blocks the PCSK9 enzyme, resulting in more LDL receptors available to remove LDL from the blood, which produces in a decrease in LDL blood levels. Commonly known PCSK9 inhibitors include but not limited to Repatha (evolocumab), Praulent (alirocumab). See “PCSK9 inhibitors: A new era of lipid lowering therapy”, Chaudhary et al., World J Cardiol.2017 Feb 26; 9(2): 76–91. “Statins”, as used herein, the term refers to a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They lower the level of cholesterol in the blood by reducing the production of cholesterol by the liver Example of statins commonly known include but not limited to Atorvastatin (Lipitor), Lovastatin (Altoprev), Pitavastatin (Livalo, Zypitamag), Pravastatin (Pravachol), Rosuvastatin (Crestor, Ezallor), and Simvastatin (Zocor). “Malignancy”, as used herein, refers to the presence of cancerous cells that have the ability to spread to other sites in the body (metastasize) or to invade nearby (locally) and destroy tissues. Malignant cells tend to have fast, uncontrolled growth and do not die normally due to changes in their genetic makeup. There are several main types of malignancy. Carcinoma is a malignancy that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a Atty. Docket No.4427-12602 malignancy that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a malignancy that begins in blood-forming tissue, such as the bone marrow, and causes too many abnormal blood cells to be made. Lymphoma and multiple myeloma are malignancies that begin in the cells of the immune system. Central nervous system cancers are malignancies that begin in the tissues of the brain and spinal cord. “Nonmelanoma Skin Cancer”, as used herein, refer to any cancer that forms in the basal, squamous or Merkel cells of the skin. Melanoma is a cancer that develops in the skin’s melanocytes. “Sponsor of study” as used herein, refers to an individual, institution, company or organization (for example, a contract research organization) that takes the responsibility to initiate, manage or finance the clinical trial but does not actually conduct the investigation. As used herein, the term “total dose” for administration means the entire amount of an active pharmaceutical ingredient such as ENPP1 polypeptide (INZ-701) intended to be administered to a subject in a single dose, wherein the dose is determined based on the subject’s body weight. In certain embodiments, the total dose is expressed in milligrams per kilogram (mg / kg) of body weight and is delivered in a form such as a pre-filled syringe or vial. A disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein the terms “alteration,” “defect,” “variation” or “mutation” refer to a mutation in a gene in a cell that affects the function, activity, expression (transcription or translation) or conformation of the polypeptide it encodes, including missense and nonsense mutations, insertions, deletions, frameshifts and premature terminations. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. A “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. As used herein, the term “immune response” or “immune reaction” refers to the host's immune system to antigen in an invading (infecting) pathogenic organism, or to introduction or expression of foreign protein. The immune response is generally humoral and local; antibodies produced by B cells combine with antigen in an antigen-antibody complex to inactivate or neutralize antigen. Immune response is often observed when human proteins are injected into Atty. Docket No.4427-12602 mouse model systems. Generally, the mouse model system is made immune tolerant by injecting immune suppressors prior to the introduction of a foreign antigen to ensure better viability. As used herein, the term “immune suppression” is a deliberate reduction of the activation or efficacy of the host immune system using immune suppressant drugs to facilitate immune tolerance towards foreign antigens such as foreign proteins, organ transplants, bone marrow and tissue transplantation. Non-limiting examples of immunosuppressant drugs include anti- CD4(GK1.5) antibody, Cyclophosphamide, Azathioprine (Imuran), Mycophenolate mofetil (Cellcept), Cyclosporine (Neoral, Sandimmune, Gengraf), Methotrexate (Rheumatrex), Leflunomide (Arava), Cyclophosphamide (Cytoxan) and Chlorambucil (Leukeran). As used herein, the term “Anti-drug antibody (ADA)”refers to any antibody produced by the immune system of a subject in response to the administration of a therapeutic agent such as ENPP1 polypeptide (INZ-701). These antibodies specifically bind to the therapeutic agent and may neutralize its activity, alter its pharmacokinetics, or otherwise affect safety or efficacy. As used herein, the term “ENPP” or “NPP” refers to ectonucleotide pyrophosphatase / phosphodiesterase. As used herein, the term “ENPP1 protein” or “ENPP1 polypeptide” refers to ectonucleotide pyrophosphatase / phosphodiesterase-1 protein encoded by the ENPP1 gene. The encoded protein is a type II transmembrane glycoprotein and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. ENPP1 protein has a transmembrane domain and soluble extracellular domain. The extracellular domain is further subdivided into somatomedin B domain, catalytic domain (residues 186 to 586 of SEQ ID NO: 1) and the nuclease domain (residues 524 to 885 of SEQ ID NO: 1). See Figure 2 and Figure 3. The term ENPP1 polypeptide also encompasses ENPP1 fusion polypeptide such as ENPP1-Fc fusion. The term ENPP1 polypeptide also encompasses mutant ENPP1 polypeptides and mutant ENPP1 fusion polypeptides. The sequence and structure of wild-type ENPP1 is described in detail in PCT Application Publication No. WO 2014 / 126965 to Braddock, et al., which is incorporated herein in its entirety by reference. Mammal ENPP1 polypeptides, mutants, or mutant fragments thereof, have been previously disclosed in International PCT Application Publications No. WO / 2014 / 126965, WO / 2016 / 187408., WO / 2017 / 087936, WO2018 / 027024, WO 2020 / 047520, WO 2020 / 206302, WO 2020 / 150716, WO 2021 / 243031, WO 2021 / 243054, WO 2021 / 252549, WO 2022 / 006545, WO 2022 / 076848, WO 2022 / 109344, WO 2023 / 196820 and WO 2023 / 049864 all of which are incorporated by reference in their entireties herein. As used herein, the term “ENPP1 precursor protein” refers to ENPP1 with its signal peptide sequence at the ENPP1 N-terminus. Upon proteolysis, the signal sequence is cleaved Atty. Docket No.4427-12602 from ENPP1 to provide the ENPP1 protein. Signal peptide sequences useful within the invention include, but are not limited to, Albumin signal sequence, Azurocidin signal sequence, ENPP1 signal peptide sequence, ENPP2 signal peptide sequence, ENPP7 signal peptide sequence, and / or ENPP5 signal peptide sequence. As used herein, the term “ENPP1-Fc construct” or “ENPP1-Fc” refers to ENPP1 recombinantly fused and / or chemically conjugated (including both covalent and non-covalent conjugations) to an FcR binding domain of an IgG molecule (preferably, a human IgG). In certain embodiments, the C-terminus of ENPP1 is fused or conjugated to the N-terminus of the FcR binding domain. As used herein, the term “Fc” refers to a human IgG (immunoglobulin) Fc domain. Subtypes of IgG such as IgG1, IgG2, IgG3, and IgG4 are contemplated for use as Fc domains. As used herein, the “Fc region or Fc polypeptide” is the portion of an IgG molecule that correlates to a crystallizable fragment obtained by papain digestion of an IgG molecule. The Fc region comprises the C-terminal half of the two heavy chains of an IgG molecule that are linked by disulfide bonds. It has no antigen binding activity but contains the carbohydrate moiety and the binding sites for complement and Fc receptors, including the FcRn receptor. The Fc fragment contains the entire second constant domain CH2 (residues 231-340 of human IgG1, according to the Kabat numbering system) and the third constant domain CH3 (residues 341- 447). The term “IgG hinge-Fc region” or “hinge-Fc fragment” refers to a region of an IgG molecule consisting of the Fc region (residues 231 -447) and a hinge region (residues 216-230) extending from the N-terminus of the Fc region. The term “constant domain” refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen binding site. The constant domain contains the CH1, CH2 and CH3 domains of the heavy chain and the CHL domain of the light chain. As used herein, the term “fragment,” as applied to a nucleic acid, refers to a subsequence of a larger nucleic acid. A “fragment” of a nucleic acid can be at least about 15, 50-100, 100- 500, 500-1000, 1000-1500 nucleotides, 1500-2500, or 2500 nucleotides (and any integer value in between). As used herein, the term “fragment,” as applied to a protein or peptide, refers to a subsequence of a larger protein or peptide, and can be at least about 20, 50, 100, 200, 300 or 400 amino acids in length (and any integer value in between). “Isolated” means altered or removed from the natural state. For example, a nucleic acid or a polypeptide naturally present in a living animal is not “isolated,” but the same nucleic acid or polypeptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. Atty. Docket No.4427-12602 As used herein, the term “patient,” “individual” or “subject” refers to a human. Preferably the patient or individual or subject is an infant between the ages of 0 day (i.e. greater than 30 minutes) and less than 12 months. (i.e. within one year of age from birth) The term includes a subject of any age or sex. The subject is an infant between the ages of greater than 30 minutes to under 12 months. (i.e. from birth to under the age of 1). As used herein, the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient. Multiple techniques of administering a compound exist in the art including, but not limited to, subcutaneous, intravenous, oral, aerosol, inhalational, rectal, vaginal, transdermal, intranasal, buccal, sublingual, parenteral, intrathecal, intragastrical, ophthalmic, pulmonary, and topical administration. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained; for example, phosphate-buffered saline (PBS). As used herein the term “plasma pyrophosphate (PPi) levels” refers to the amount of pyrophosphate present in plasma of animals. In certain embodiments, animals include rat, mouse, cat, dog, human, cow and horse. It is necessary to measure PPi in plasma rather than serum because of release from platelets. There are several ways to measure PPi, one of which is by enzymatic assay using uridine-diphosphoglucose (UDPG) pyrophosphorylase (Lust & Seegmiller, 1976, Clin. Chim. Acta 66:241-249; Cheung & Suhadolnik, 1977, Anal. Biochem. 83:61-63) with modifications. Typically, normal PPi levels in healthy subjects range from about 1µm to about 3 µM, in some cases between 1-2 µm. Subjects who have defective ENPP1 expression tend to exhibit low PPi levels which range from at least 10% below normal levels, at least 20% below normal levels, at least 30% below normal levels, at least 40% below normal levels, at least 50% below normal levels, at least 60% below normal levels, at least 70% below normal levels, at least 80% below normal levels and combinations thereof. In patients afflicted with GACI, the PPi levels are found to be less than 1 µm and in some cases are below the level of detection. In patients afflicted with PXE, the PPi levels are below 0.5 µm. (Arterioscler Thromb Vasc Biol.2014 Sep;34(9):1985-9; Braddock et al., Nat Commun.2015; 6: 10006.) As used herein, the term “polypeptide” refers to a polymer composed of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof linked via peptide bonds. As used herein, the term “PPi” refers to pyrophosphate. Atty. Docket No.4427-12602 As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. “Sample” or “biological sample” as used herein means a biological material isolated from a subject. The biological sample may contain any biological material suitable for detecting a mRNA, polypeptide or other marker of a physiologic or pathologic process in a subject, and may comprise fluid, tissue, cellular and / or non-cellular material obtained from the individual. As used herein, “substantially purified” refers to being essentially free of other components. For example, a substantially purified polypeptide is a polypeptide that has been separated from other components with which it is normally associated in its naturally occurring state. Non-limiting embodiments include 95% purity, 99% purity, 99.5% purity, 99.9% purity and 100% purity. As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound useful within the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder, a symptom of a disease or disorder or the potential to develop a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, the symptoms of the disease or disorder, or the potential to develop the disease or disorder. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. The terms “prevent,” “preventing,” and “prevention”, as used herein, refer to inhibiting the inception or decreasing the occurrence of a disease in a subject. Prevention may be complete (e.g., the total absence of pathological cells in a subject) or partial. Prevention also refers to a reduced susceptibility to a clinical condition. As used herein, the term “wild-type” refers to a gene or gene product isolated from a naturally occurring source. A wild-type gene is most frequently observed in a population and is thus arbitrarily designed the “normal” or “wild-type” form of the human NPP1 genes. In contrast, the term “functionally equivalent” refers to a NPP1 gene or gene product that displays modifications in sequence and / or functional properties (i.e., altered characteristics) when compared to the wild-type gene or gene product. Naturally occurring mutants can be isolated; these are identified by the fact that they have altered characteristics (including altered nucleic acid sequences) when compared to the wild-type gene or gene product. The term “functional equivalent variant”, as used herein, relates to a polypeptide substantially homologous to the sequences of ENPP1 (defined above) and that preserves the Atty. Docket No.4427-12602 enzymatic and biological activities of ENPP1. Methods for determining whether a variant preserves the biological activity of the native ENPP1 are widely known to the skilled person and include any of the assays used in the experimental part of said application. Particularly, functionally equivalent variants of ENPP1 delivered by viral vectors is encompassed by the present invention. The functionally equivalent variants of ENPP1 are polypeptides substantially homologous to the native ENPP1. The expression “substantially homologous”, relates to a protein sequence when said protein sequence has a degree of identity with respect to the ENPP1 sequences described above of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% respectively. The degree of identity between two polypeptides is determined using computer algorithms and methods that are widely known for the persons skilled in the art. The identity between two amino acid sequences is preferably determined by using the BLASTP algorithm (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md.20894, Altschul, S., et al., J. Mol. Biol.215: 403-410 (1990)), though other similar algorithms can also be used. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. “Functionally equivalent variants” of ENPP1 may be obtained by replacing nucleotides within the polynucleotide accounting for codon preference in the host cell that is to be used to produce the ENPP1 respectively. Such “codon optimization” can be determined via computer algorithms which incorporate codon frequency tables such as “Human high.cod” for codon preference as provided by the University of Wisconsin Package Version 9.0, Genetics Computer Group, Madison, Wis. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±10% or ±5%, in certain embodiments ±1-5%, in certain embodiments ±5%, in certain embodiments ±4% , in certain embodiments ±4%, in certain embodiments ±3%, in certain embodiments ±2%, and in certain embodiments ±1% from the specified value (2.4 mg / kg), as such variations are appropriate to perform the disclosed methods. The disclosure provides a representative example of protein sequences. The protein sequences described can be converted into nucleic acid sequences by performing revere translation and codon optimization. There are several tools available in art such as Expasy (https: / / www.expasy.org / ) and bioinformatics servers (http: / / www.bioinformatics.org)that enable such conversions Atty. Docket No.4427-12602 Ranges: throughout this disclosure, various aspects according to the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope according to the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Preferred methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the presently disclosed methods and compositions. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. ABCC6 Mutation detection Genomic DNA is isolated from peripheral blood samples of subjects suspected of having ABC66 deficiency using commercially available DNA isolation kits. (Puregene DNA Isolation Kit; Gentra Systems, Minneapolis, Minnesota, USA). Control genomic DNA is obtained from the human lymphoblastoid cell line K562 (American Type Culture Collection, Manassas, Virginia, USA). All DNA samples are adjusted with water to a concentration of 10 ng / μL. The mutation‐detection strategy is based on: (1) identification of the recurrent mutations R1141X and del23–29 by restriction‐enzyme digestion; (2) optimised denaturing high‐ performance liquid chromatography (dHPLC) scanning of PCR products corresponding to all exons in subjects in whom the two recurrent mutations are not identified on both alleles, followed by (3) sequencing of exons with altered dHPLC patterns; and (4) confirmation of novel mutations by restriction‐enzyme digestion or resequencing. Screening for the recurrent mutations R1141X and del23–29 is performed as previously described. (Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum. Ringpfeil F, Nakano A, Uitto J, Pulkkinen L, Am J Hum Genet.2001 Mar; 68(3):642-52.) Conditions and primers for generating PCR products spanning all exons of the coding regions and flanking intronic sequences of the ABCC6 gene are identified for optimum dHPLC screening in supplementary table (J Med Genet.2007 Oct; 44(10): 621–628.). These primers are designed to exclude the pseudogenes homologous to exons 1–4 and 1– 931 and to anneal within ∼50 bases of the 5′ and 3′ ends of the exon and to exclude known intronic polymorphisms where possible. PCR for dHPLC analysis is performed using 1.5 U Taq polymerase (Qiagen Inc., Valencia, California, USA) mixed with 5 U Optimase Taq polymerase Atty. Docket No.4427-12602 (Transgenomic, Gaithersburg, Maryland, USA) and Q buffer (Qiagen), according to the manufacturer' instructions. PCR reactions contained 200 ng DNA as template and 20 ng of each primer in a final volume of 50 μl. Cycling conditions for all primer pairs were 94°C for 5 min, followed by 41 cycles of 94°C for 1 min, annealing temperature for a particular primer pair (range 55–60°C) for 1 min and 72°C for 1 min, with a final step at 72°C for 5 min. The PCR products generated using patients with PXE DNA as template are allowed to form heteroduplexes with an equal volume of a PCR product of the same exon amplified from template DNA of the lymphoblastoid control cell line K562. For this purpose, the PCR products were mixed in a 1:1 ratio and denatured at 94°C for 10 min, followed by reannealing at 65°C for 15 min and 37°C for 15 min. The PCR products are then screened by dHPLC (WAVE; Transgenomic, Gaithersburg, Maryland, USA) using methods designed to enhance partial denaturation of the PCR products containing mismatched bases (see supplementary table 1 of J Med Genet.2007 Oct; 44(10): 621–628.). PCR products showing pattern shifts are sequenced in both directions in most cases. DNA sequencing is performed on an automated sequencer (ABI Prism 377 or ABI 3100; Perkin‐Elmer‐Cetus, Foster City, California, USA). Putative mutations are confirmed by restriction‐enzyme digestion followed by agarose‐gel electrophoresis or by resequencing of a new PCR product when a suitable restriction enzyme was not available. The subjects are then identified as subjects with ABCC6 mutations if they were found to contain known mutations in ABCC6 genes that affect the activity and or expression level of ABCC6 protein. DETAILED DESCRIPTION 1. Overview The disclosure provides for treating, preventing, or reducing the progression rate and / or severity of pathologic calcification and / or ossification or one or more complications of pathologic calcification and / or ossification by administering to a subject ENPP1-Fc subcutaneously (SC) at a dose of about 2.4 mg / kg. With respect to a recited dose of ENPP1-Fc, “about” mean a degree of error given the nature or precision of the measurements within ±5 percent (%), ±4%, ±3%, or ±2% or ±1%of the recited dose in mg ENPP1-FC / kg body weight of the subject. 2. Administered Dose of ENPP1 Agent An ENPP1 agent is administered at a dose of about 2.4 mg / kg. A medical practitioner will select which of these doses is administered to a given subject and may be guided by a subject’s serum PPi levels, the selected dose being sufficient to restore PPi to normal levels in the subject. The subject is an infant of age that is greater than 30 minutes and less than 12 months, i.e. upto 11 months and 29 days. The infant can be administered ENPP1 agent at a dosage of 2.4 mg / kg, right after birth but preferably at least 30 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 150 minutes, at least 3 hours, at least 4 hours, at Atty. Docket No.4427-12602 least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours or at least 24 hours after birth. This disclosure describes methods for administering a total dose of 2.4 mg of ENPP1 polypeptide per kilogram (kg) of an infant’s body weight. This total dosage can be delivered using different dosing schedules, depending on clinical needs and treatment goals. For example, one approach involves administering 1.2 mg / kg of ENPP1 polypeptide twice per week, resulting in a total weekly dose of 2.4 mg / kg. Another option is to administer 0.8 mg / kg three times per week, which also adds up to 2.4 mg / kg per week. Alternatively, the dose can be divided into 0.6 mg / kg given four times per week, or 0.4 mg / kg administered six times per week—both of which achieve the same total weekly dose of 2.4 mg / kg. These flexible dosing strategies allow healthcare providers to tailor treatment plans to the specific needs of each infant while maintaining consistent therapeutic exposure of 2.4 mg of ENPP1 polypeptide per kg bodyweight. 3. ENPP1 Agent An ENPP1 agent is an ENPP1 polypeptide. ENPP1 polypeptides disclosed herein include naturally occurring polypeptides of the ENPP1 family as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a biological activity. The terms “ENPP1” or “ENPP1 polypeptide” refers to ectonucleotide pyrophosphatase / phosphodiesterase 1 proteins (NPP1 / ENPP1 / PC-1) and ENPP1-related proteins, derived from any species. ENPP1 protein comprises a type II transmembrane glycoprotein that forms a homodimer. Each monomer of the ENPP1 protein comprises a short intracellular N-terminal domain involved in targeting to the plasma membrane, a transmembrane domain, and a large extracellular region comprising several domains. The large extracellular region comprises SMB1 and SMB2 domains, which have been reported to take part in ENPP1 dimerization (R. Gijsbers, H. et al., Biochem. J.371; 2003: 321–330). Specifically, the SMB domains contain eight cysteine residues, each arranged in four disulphide bonds, and have been shown to mediate ENPP1 homodimerization through covalent cystine inter- and intramolecular bonds. The protein cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. ENPP1 protein functions to hydrolyze nucleoside 5’ triphosphatase to either corresponding monophosphates and also hydrolyzes diadenosine polyphosphates. ENPP1 proteins play a role in purinergic signaling which is involved in the regulation of cardiovascular, neurological, immunological, musculoskeletal, hormonal, and hematological functions. An exemplary amino acid sequence of the human ENPP1 precursor protein (NCBI accession NP_006199) is shown in Figure 2 (SEQ ID NO: 1). The human ENPP1 precursor protein includes an endogenous ENPP1 signal peptide sequence at the ENPP1 N-terminus. Numbering Atty. Docket No.4427-12602 of amino acids for all ENPP1-related polypeptides described herein is based on the numbering of the human ENPP1 precursor protein sequence provided in Figure 2 unless specifically designated otherwise. In certain embodiments, the ENPP1 precursor protein further comprises an endogenous or heterologous signal peptide sequence. Upon proteolysis, the signal peptide sequence is cleaved from the ENPP1 precursor protein to provide the mature ENPP1 protein. See, e.g., Jansen S, et al. J Cell Sci.2005;118(Pt 14):3081-9. Exemplary signal peptide sequences that can be used with the polypeptides disclosed herein include, but are not limited to, ENPP1 signal peptide sequence, ENPP2 signal peptide sequence, ENPP7 signal peptide sequence, and / or ENPP5 signal peptide sequence. The processed (mature) extracellular ENPP1 polypeptide sequence is shown in Figure 4 (SEQ ID NO: 2). It is generally known in the art that ENPP1 is well-conserved among vertebrates, with large stretches of the extracellular domain substantially conserved. For example, Figure 5A and Figure 5B depict a multi-sequence alignment of a human ENPP1 extracellular domain compared to various ENPP1 orthologs. ENPP1 binding to various nucleotide triphosphates (e.g., ATP, UTP, GTP, TTP, and CTP), pNP-TMP, 3',5'-cAMP, and 2'-3'-cGAMP is also highly conserved (see, e.g., Kato K. et al., Proc Natl Acad Sci USA.2012;109(42):16876-81 and Mackenzie NC, et al. Bone.2012;51(5):961-8). Accordingly, from these alignments, it is possible to predict key amino acid positions with the extracellular domain that are important for normal ENPP1 activities as well as to predict amino acid positions that are likely to be tolerant to substitution without significantly altering normal ENPP1 activities. Therefore, an enzymatically active, human ENPP1 polypeptide useful in accordance with the presently disclosed compositions, may include one or more amino acids at corresponding positions from the sequence of another vertebrate ENPP1, or may include a residue that is similar to that in the human or other vertebrate sequences. Substitutions of one or more amino acids at corresponding positions may include conservative variations or substitutions that are not likely to change the shape of the polypeptide chain or alter normal ENPP1 activities. Examples of conservative variations, or substitutions, include the replacement of one hydrophobic residue such as isoleucine, valine, leucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acid, or glutamine for asparagine. For example, ENPP1 polypeptides include polypeptides derived from the sequence of any known ENPP1 polypeptide having a sequence at least about 80% identical to the sequence of an ENPP1 polypeptide, and preferably at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater identity. 4. Enzymatic Activity of ENPP1 ENPP1 proteins have been characterized in the art in terms of structural and biological characteristics. In certain embodiments, soluble ENPP1 proteins disclosed herein comprise pyrophosphatase and / or phosphodiesterase activity. For instance, in some embodiments, the ENPP1 protein binds nucleotide triphosphates (e.g., ATP, UTP, GTP, TTP, and CTP), pNP- Atty. Docket No.4427-12602 TMP, 3',5'-cAMP, and 2'-3'-cGAMP; and converts nucleotide triphosphates into inorganic pyrophosphate [see, e.g., Kato K. et al., Proc Natl Acad Sci USA.2012;109(42):16876-81; Li L, et al. Nat Chem Biol.2014;10(12):1043-8; Jansen S, et al. Structure.2012;20(11):1948-59; and Onyedibe KI, et al. Molecules.2019;24(22)]. “Enzymatically active” or “Biologically active” ENPP1 polypeptides exhibit pyrophosphatase and / or phosphodiesterase activity (e.g., is capable of binding and / or hydrolyzing ATP into AMP and PPi and / or AP3a into ATP). For example, the pyrophosphatase / phosphodiesterase domain of an ENPP1 protein hydrolyzes extracellular nucleotide triphosphates to produce inorganic pyrophosphates (PPi) and is generally soluble. This activity can be measured using a pNP-TMP assay as previously described (Saunders, et al., 2008, Mol. Cancer Ther.7(10):3352-62; Albright, et al., 2015, Nat Comm.6:10006). In certain embodiments, the soluble ENPP1 polypeptide has a kcat value for the substrate ATP greater than or equal to about 3.4 (±0.4) s'1enzyme'1, wherein the kcat is determined by measuring the rate of hydrolysis of ATP for the polypeptide. In certain embodiments, the soluble ENPP1 polypeptide has a KM value for the substrate ATP less than or equal to about 2 µM, wherein the KM is determined by measuring the rate of hydrolysis of ATP for the polypeptide. In addition to the teachings herein, these references provide ample guidance for how to generate soluble ENPP1 proteins that retain one or more biological activities (e.g., conversion of nucleotides into inorganic pyrophosphate). 5. Soluble ENPP1 In one embodiment, the disclosure relates to ENPP1 polypeptides. As described herein, the term soluble ENPP1 polypeptide, includes any naturally occurring extracellular domain of an ENPP1 protein as well as any variants thereof (including mutants, fragments and peptidomimetic forms) that retain a biological activity (e.g., enzymatically active). Examples of soluble ENPP1 polypeptides include, for example, an ENPP1 extracellular domain (SEQ ID NO: 2) as shown in Figure 4. In certain embodiments, the soluble ENPP1 polypeptides further comprise a signal sequence in addition to the extracellular domain of an ENPP1 polypeptide. Exemplary signal sequences include the native signal sequence of an ENPP1 polypeptide, or a signal sequence from another protein, such as a hENPP7 signal sequence. Examples of variant soluble ENPP1 polypeptides are provided in International Patent Application Publication Nos. WO 2012 / 125182, WO 2014 / 126965, WO 2016 / 187408, WO 2018 / 027024, WO 2020206302 and WO 2020 / 047520 the contents of all of which are incorporated herein by reference in their entirety. 6. ENPP1 Fusion Proteins In some embodiments, the ENPP1 polypeptide is a fusion protein comprising an ENPP1 polypeptide domain and one or more heterologous protein portions (i.e., polypeptide domains heterologous to ENPP1). An amino acid sequence is understood to be heterologous to ENPP1 if it is not uniquely found in the form of ENPP1 represented by SEQ ID NO: 1. In some Atty. Docket No.4427-12602 embodiments, the heterologous protein portion comprises an Fc domain of an immunoglobulin. In some embodiments, the Fc domain of the immunoglobulin is an Fc domain of an IgG1 immunoglobulin. In certain embodiments, the soluble ENPP1 polypeptide is C-terminally fused to the Fc domain of human immunoglobulin 1 (IgGl), human immunoglobulin 2 (IgG2), human immunoglobulin 3 (IgG3), and / or human immunoglobulin 4 (IgG4). In other embodiments, the soluble ENPP1 polypeptide is N-terminally fused to the Fc domain of human immunoglobulin 1 (IgGl), human immunoglobulin 2 (IgG2), human immunoglobulin 3 (IgG3), and / or human immunoglobulin 4 (IgG4). In some embodiments, the presence of an Fc domain improves half- life, solubility, reduces immunogenicity, and increases the activity of the soluble ENPP1 polypeptide. In certain embodiments, portions of the native human IgG proteins (IgG1, IgG2, IgG3, and IgG4), may be used for the Fc portion (e.g., ENPP1-Fc). For instance, the present disclosure provides fusion proteins comprising ENPP1 fused to a polypeptide comprising a constant domain of an immunoglobulin, such as a CH1, CH2, or CH3 domain derived from human IgG1, IgG2, IgG3, and / or IgG4. The Fc fragment may comprise regions of the native IgG such as the hinge region (residues 216- 230 of human IgG1, according to the Rabat numbering system), the entire second constant domain CH2 (residues 231-340), and the third constant domain CH3 (residues 341- 447). As used herein, the term “ENPP1-Fc construct” refers to a soluble form of ENPP1 (e.g., the extracellular domain of an ENPP1 polypeptide) recombinantly fused and / or chemically conjugated (including both covalent and non-covalent conjugations) to an FcR binding domain of an IgG molecule (preferably, a human IgG). In certain embodiments, the C-terminus of ENPP1 is fused or conjugated to the N-terminus of the FcR binding domain. An example of an amino acid sequence that may be used for the Fc portion of human IgG1 (G1Fc) is SEQ ID NO: 6 (Table 1). In part, the disclosure provides polypeptides comprising, consisting essential of, or consisting of amino acid sequences with 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 6. In some embodiments, the heterologous protein portion comprises one or more domains selected from the group consisting of polyhistidine, FLAG tag, Glu-Glu, glutathione S- transferase (GST), thioredoxin, protein A, protein G, an immunoglobulin heavy-chain constant region (Fc), maltose binding protein (MBP), or human serum albumin. A fusion domain may be selected so as to confer a desired property. For example, some fusion domains are particularly useful for isolation of the fusion proteins by affinity chromatography. For the purpose of affinity purification, relevant matrices for affinity chromatography, such as glutathione-, amylase-, and nickel- or cobalt- conjugated resins are used. Many of such matrices are available in “kit” form, such as the Pharmacia GST purification system and the QIAexpressTMsystem (Qiagen) useful with (HIS6) fusion partners. As another example, a fusion domain may be selected so as to facilitate detection of the ENPP1 polypeptide. Examples of such detection domains include the Atty. Docket No.4427-12602 various fluorescent proteins (e.g., GFP) as well as “epitope tags,” which are usually short peptide sequences for which a specific antibody is available. Well-known epitope tags for which specific monoclonal antibodies are readily available include FLAG, influenza virus haemagglutinin (HA), and c-myc tags. In some cases, the fusion domains have a protease cleavage site, such as for Factor Xa or thrombin, which allows the relevant protease to partially digest the fusion proteins and thereby liberate the recombinant proteins therefrom. The liberated proteins can then be isolated from the fusion domain by subsequent chromatographic separation. 7. Linkers In some embodiments, the ENPP1 fusion protein further comprises a linker positioned between the ENPP1 polypeptide domain and the one or more heterologous protein portions (e.g., an Fc immunoglobulin domain). In certain embodiments, the soluble ENPP1 polypeptide is directly or indirectly fused to the Fc domain. In some embodiments, the soluble ENPP1 fusion protein comprises a linker between the Fc domain and the ENPP1 polypeptide. In some embodiments, a linker can be an amino acid spacer including 1-200 amino acids. Suitable peptide spacers are known in the art, and include, for example, peptide linkers containing flexible amino acid residues such as glycine, alanine, and serine. In some embodiments, the linker comprises a polyglycine linker or a Gly-Ser linker. In some embodiments, a spacer can contain motifs, e.g., multiple or repeating motifs, of GA (SEQ ID NO: 21), GS (SEQ ID NO: 22), GG (SEQ ID NO: 23), GGA (SEQ ID NO: 24), GGS (SEQ ID NO: 25), GGG (SEQ ID NO: 26), GGGA (SEQ ID NO: 27), GGGS (SEQ ID NO: 28), GGGG (SEQ ID NO: 29), GGGGA (SEQ ID NO: 30), GGGGS (SEQ ID NO: 31), GGGGG (SEQ ID NO: 32), GGAG (SEQ ID NO: 33), GGSG (SEQ ID NO: 34), AGGG (SEQ ID NO: 35), SGGGG (SEQ ID NO: 36), or SGGG (SEQ ID NO: 37). In some embodiments, a spacer can contain 2 to 12 amino acids including motifs of GA or GS, e.g., GA, GS, GAGA (SEQ ID NO: 38), GSGS (SEQ ID NO: 39), GAGAGA (SEQ ID NO: 40), GSGSGS (SEQ ID NO: 41), GAGAGAGA (SEQ ID NO: 42), GSGSGSGS (SEQ ID NO: 43), GAGAGAGAGA (SEQ ID NO: 44), GSGSGSGSGS (SEQ ID NO: 45), GAGAGAGAGAGA (SEQ ID NO: 46), and GSGSGSGSGSGS (SEQ ID NO: 47). In some embodiments, a spacer can contain 3 to 12 amino acids including motifs of GGA or GGS, e.g., GGA, GGS, GGAGGA (SEQ ID NO: 48), GGSGGS (SEQ ID NO: 49), GGAGGAGGA (SEQ ID NO: 50), GGSGGSGGS (SEQ ID NO: 51), GGAGGAGGAGGA (SEQ ID NO: 52), and GGSGGSGGSGGS (SEQ ID NO: 53). In yet some embodiments, a spacer can contain 4 to 12 amino acids including motifs of GGAG (SEQ ID NO: 54), GGSG (SEQ ID NO: 55), e.g., GGAG (SEQ ID NO: 56), GGSG (SEQ ID NO: 57), GGAGGGAG (SEQ ID NO: 58), GGSGGGSG (SEQ ID NO: 59), GGAGGGAGGGAG (SEQ ID NO: 60), and GGSGGGSGGGSG (SEQ ID NO: 61). In some embodiments, a spacer can contain motifs of GGGGA (SEQ ID NO: 62) or GGGGS (SEQ ID NO: 63), e.g., GGGGAGGGGAGGGGA (SEQ ID NO: 64) and GGGGSGGGGSGGGGS (SEQ ID NO: 65). In some embodiments of the invention, an amino acid spacer between a heterologous protein portion (e.g., an Fc domain monomer, a wild-type Fc domain, an Fc domain with amino acid substitutions (e.g., one or more Atty. Docket No.4427-12602 substitutions that reduce dimerization), an albumin-binding peptide, a fibronectin domain, or a human serum albumin) and a soluble ENPP1 polypeptide may be GGG, GGGA (SEQ ID NO: 27), GGGG (SEQ ID NO: 29), GGGAG (SEQ ID NO: 66), GGGAGG (SEQ ID NO: 67), or GGGAGGG (SEQ ID NO: 68). In some embodiments, a spacer can also contain amino acids other than glycine, alanine, and serine, e.g., LIN (SEQ ID NO: 69), TGGGG (SEQ ID NO: 70), AAAL (SEQ ID NO: 71), AAAK (SEQ ID NO: 72), AAAR (SEQ ID NO: 73), EGKSSGSGSESKST (SEQ ID NO: 74), GSAGSAAGSGEF (SEQ ID NO: 75), AEAAAKEAAAKA (SEQ ID NO: 76), KESGSVSSEQLAQFRSLD (SEQ ID NO: 77), GENLYFQSGG (SEQ ID NO: 78), SACYCELS (SEQ ID NO: 79), RSIAT (SEQ ID NO: 80), RPACKIPNDLKQKVMNH (SEQ ID NO: 81), GGSAGGSGSGSSGGSSGASGTGTAGGTGSGSGTGSG (SEQ ID NO: 82), AAANSSIDLISVPVDSR (SEQ ID NO: 83), GGSGGGSEGGGSEGGGSEGGGSEGGGSEGGGSGGGS (SEQ ID NO: 84), NSS (SEQ ID NO: 87), ESS (SEQ ID NO: 88), RQQ (SEQ ID NO: 89), KR (SEQ ID NO: 90), (R)m; m=0-15 (SEQ ID NO: 91), DSSSEEKFLRRIGRFG (SEQ ID NO: 92), EEEEEEEPRGDT (SEQ ID NO: 93), APWHLSSQYSRT (SEQ ID NO: 94), STLPIPHEFSRE (SEQ ID NO: 95), VTKHLNQISQSY (SEQ ID NO: 96), (E)m; m=1-15 (SEQ ID NO: 97), RSGSGGS (SEQ ID NO: 98), (D)m; m=1-15 (SEQ ID NO: 99), LVIMSLGLGLGLGLRK (SEQ ID NO: 100), VIMSLGLGLGLGLRK (SEQ ID NO: 101), IMSLGLGLGLGLRK (SEQ ID NO: 102), MSLGLGLGLGLRK (SEQ ID NO: 103), SLGLGLGLGLRK (SEQ ID NO: 104), LGLGLGLGLRK (SEQ ID NO: 105), GLGLGLGLRK (SEQ ID NO: 106), LGLGLGLRK (SEQ ID NO: 107), GLGLGLRK (SEQ ID NO: 108), LGLGLRK (SEQ ID NO: 109), GLGLRK (SEQ ID NO: 110), LGLRK (SEQ ID NO: 111), GLRK (SEQ ID NO: 112), LRK (SEQ ID NO: 113), RK (SEQ ID NO: 114), or (K)m; m=1-15 (SEQ ID NO: 115). In some embodiments, a spacer can contain motifs, e.g., multiple or repeating motifs, of EAAAK (SEQ ID NO: 85). In some embodiments, a spacer can contain motifs, e.g., multiple or repeating motifs, of praline- rich sequences such as (XP)n, in which X may be any amino acid (e.g., A, K, or E) and n is from 1-5, and PAPAP (SEQ ID NO: 86). The length of the peptide spacer and the amino acids used can be adjusted depending on the two proteins involved and the degree of flexibility desired in the final protein fusion polypeptide. The length of the spacer can be adjusted to ensure proper protein folding and avoid aggregate formation. In some embodiments, different elements of the fusion proteins (e.g., immunoglobulin Fc fusion proteins) may be arranged in any manner that is consistent with desired functionality. For example, a soluble ENPP1 polypeptide domain may be placed C-terminal to a heterologous protein portion, or alternatively, a heterologous protein portion may be placed C-terminal to a soluble ENPP1 polypeptide domain. The soluble ENPP1 polypeptide domain and the heterologous protein portion may be directly or indirectly linked in a fusion protein, and Atty. Docket No.4427-12602 additional domains or amino acid sequences may be included C- or N-terminal to either domain or between the domains. Preferred fusion proteins comprise the amino acid sequence set forth in any one of SEQ ID NOs: 3-5. In some embodiments, soluble ENPP1 polypeptides of the present disclosure contain one or more heterologous moieties. Optionally, a soluble ENPP1 polypeptide includes one or more heterologous moieties selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent. In some embodiments, a soluble ENPP1 polypeptide disclosed herein is further modified. Such modifications include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. As a result, the soluble ENPP1 polypeptide may contain non-amino acid elements, such as polyethylene glycols, lipids, polysaccharide or monosaccharide, and phosphates. Effects of such non-amino acid elements on the functionality of a soluble ENPP1 polypeptide may be tested as described herein for other soluble ENPP1 polypeptides. When a polypeptide of the disclosure is produced in cells by cleaving a nascent form of the polypeptide, post-translational processing may also be important for correct folding and / or function of the protein. Different cells (e.g., CHO, HeLa, MDCK, 293, WI38, NIH-3T3 or HEK293) have specific cellular machinery and characteristic mechanisms for such post- translational activities and may be chosen to ensure the correct modification and processing of the soluble ENPP1 polypeptides. As used herein, percent “identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, or CLUSTAL OMEGA software. In some embodiments, alignment is performed using the CLUSTAL OMEGA software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. 8. Enzymatic Activity In some embodiments, the activity of soluble ENPP1 polypeptides may also be tested in a cell-based or in vivo assay. For example, the effect of a soluble ENPP1 polypeptide on the production of inorganic pyrophosphates (PPi) can be measured. Specifically, the pyrophosphatase / phosphodiesterase domain of an ENPP1 protein hydrolyzes extracellular nucleotide triphosphates to produce inorganic pyrophosphates (PPi) and is generally soluble. Atty. Docket No.4427-12602 This activity can be measured using a pNP-TMP assay as well as an HPLC-based ATP hydrolysis assay, as previously described (Saunders, et al., 2008, Mol. Cancer Ther.7(10):3352- 62; Albright, et al., 2015, Nat Comm.6:10006). The effect of soluble ENPP1 polypeptides on the expression of genes involved in ENPP1 associated diseases such as ARHR2 (e.g., transcription of fibroblast growth factor 23 in osteoblasts and osteoclasts) can be assessed. This may, as needed, be performed in the presence of one or more nucleotide triphosphates or other ENPP1 substrates, and cells may be transfected so as to produce a soluble ENPP1 polypeptide. Likewise, a soluble ENPP1 polypeptide may be administered to a mouse or other animal and effects on ENPP1 associated diseases may be assessed using art-recognized methods. In some embodiments, ENPP1 polypeptides to be used in accordance with the methods described herein are isolated polypeptides. As used herein, an isolated protein or polypeptide is one which has been separated from a component of its natural environment. In some embodiments, a polypeptide of the disclosure is purified to greater than 95%, 96%, 97%, 98%, or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) analyses. Methods for assessment of purity are well known in the art [see, e.g., Flatman et al., (2007) J. Chromatogr. B 848:79-87]. In some embodiments, soluble ENPP1 polypeptides to be used in accordance with the methods described herein are recombinant polypeptides. 9. ENPP1 Production ENPP1 polypeptides of the disclosure can be produced by a variety of art-known techniques. For example, polypeptides of the disclosure can be synthesized using standard protein chemistry techniques such as those described in Bodansky, M. Principles of Peptide Synthesis, Springer Verlag, Berlin (1993) and Grant G. A. (ed.), Synthetic Peptides: A User's Guide, W. H. Freeman and Company, New York (1992). In addition, automated peptide synthesizers are commercially available (e.g., Advanced ChemTech Model 396; Milligen / Biosearch 9600). Alternatively, the polypeptides of the disclosure, including fragments or variants thereof, may be recombinantly produced using various expression systems [e.g., E. coli, Chinese Hamster Ovary (CHO) cells, COS cells, baculovirus, Yeast Pichia] as is well known in the art. The protein can be produced in either adherent or suspension cells. In some embodiments, the fusion protein is expressed in CHO cells. To establish stable cell lines the nucleic acid sequence encoding ENPP1 constructs are cloned into an appropriate vector for large scale protein production. In a further embodiment, the modified or unmodified polypeptides of the disclosure may be produced by digestion of recombinantly produced full-length ENPP1 polypeptides by using, for example, a protease, e.g., trypsin, thermolysin, chymotrypsin, pepsin, or paired basic amino acid converting enzyme (PACE). Computer analysis (using commercially available software, e.g., MacVector, Omega, PCGene, Molecular Simulation, Inc.) can be used to identify proteolytic cleavage sites. Alternatively, such polypeptides may be produced from Atty. Docket No.4427-12602 recombinantly generated full-length ENPP1 polypeptides using chemical cleavage (e.g., cyanogen bromide, hydroxylamine, etc.). 10. Expression Systems Many expression systems are known and can be used for the production of ENPP1 fusion protein, including bacteria (for example E. coli and Bacillus subtilis), yeasts (for example Saccharomyces cerevisiae, Kluyveronmyces lactis and Pichia pastoris), filamentous fungi (for example Aspergillus), plant cells, animal cells and insect cells. The desired protein can be produced in conventional ways, for example from a coding sequence inserted in the host chromosome or on a free plasmid. The yeasts can be transformed with a coding sequence for the desired protein in any of the usual ways (e.g., electroporation). Methods for transformation of yeast by electroporation are disclosed in Becker & Guarente, 1990, Methods Enzymol. 194: 182. Successfully transformed cells, i.e., cells that contain a DNA construct of the present disclosure, can be identified by well-known techniques. For example, cells resulting from the introduction of an expression construct can be grown to produce an ENPP1 polypeptide. Cells can be harvested and lysed, and their DNA content examined for the presence of the DNA using a method, such as that described by Southern, 1975, J. Mol. Biol, 98:503 and / or Berent, et al., 1985, Biotech 3:208. Alternatively, the presence of the protein in the supernatant can be detected using antibodies. Useful yeast plasmid vectors include pRS403—406 and pRS413—416 and are generally available front Stratagene Cloning Systems, La Jolla, CA, USA Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (Yips) and incorporate the yeast selectable markers I-11S3, TRP1, LEU2 and 1JRA3. Plasmids pRS413— 416 are Yeast Centromere plasmids (YCps). A variety of methods have been developed to operably link DNA to vectors via complementary cohesive termini. For instance, complementary homopolymer tract can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules. Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. The DNA segment, generated by endonuclease restriction digestion, is treated with bacteriophage T4 DNA polymerase or E. coli DNA polymerase I, which are enzymes that remove protruding, 3'-single-stranded termini with their 3'-5' - exonucleolytic activities, and fill in recessed 3'-ends with their polymerizing activities. The combination of these activities thus generates blunt-ended DNA segments. The blunt-ended segments are then incubated with a large molar excess of linker molecules in the Atty. Docket No.4427-12602 presence of an enzyme that is able to catalyze the ligation of blunt-ended DNA molecules, such as bacteriophage T4 DNA ligase. As a result, the products of the reaction are DNA segments carrying polymeric linker sequences at their ends. These DNA segments can be cleaved with an appropriate restriction enzyme and ligated to an expression vector that has been cleaved with an enzyme that produces termini compatible with those of the DNA segment. Clones of single, stably transfected cells are then established and screened for high expressing clones of the desired ENPP1 fusion protein. Screening of the single cell clones for ENPP1 protein expression can be accomplished in a high-throughput manner in 96 well plates using the synthetic enzymatic substrate pNP-TMP as previously described (Albright, et al., 2015, Nat. Commun.6:10006). Upon identification of high expressing clones through screening, protein production can be accomplished in shaking flasks or bioreactors are previously described in Albright, et al., 2015, Nat. Commun.6:10006. 11. ENPP1 Purification Purification of ENPP1 can be accomplished using a combination of standard purification techniques known in the art. Following purification, ENPP1-Fc can be dialyzed into PBS supplemented with Zn2+ and Mg2+ (PBSplus) concentrated to between 5 and 7 mg / ml, and frozen at -80 °C in aliquots of 200-500 pl. Aliquots can be thawed immediately prior to use and the specific activity of the solution can be adjusted to 31.25 au / ml (or about 0.7 mg / ml depending on the preparation) by dilution in PBSplus. 12. Route and Frequency of Administration The polypeptide may be administered acutely or chronically to the subject. In certain embodiments, a second dosage of a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein is administered after a suitable time interval of about after two days, after four days, after a week, or after a month to the subject or even less frequently, such as once every several months or even once a year or less. The frequency of the dose is readily apparent to the skilled artisan and depends upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, and the type and age of the patient. A dose amount or frequency may be selected so that the steady state level of plasma PPi is maintained at a constant or steady state level, and / or so as to achieve a continuous level of plasma PPi that is either close to the normal (1-3 µM) level or above (30-50% higher than) normal levels of PPi and does not return to the lower level of PPi that the subject had prior to the administration of first dosage of constructs disclosed herein. Subjects having ENPP1 deficiency have PPi levels that are less than 1 µm, in some instances, less than 0.5 µm. Atty. Docket No.4427-12602 Alternative, the ENPP1 agent may be administered at appropriate time intervals of either every 2 days, or every 4 days, every week or biweekly or once every three weeks or once every month so as to achieve a constant level of enzymatic activity of ENPP1. Alternatively, an ENPP1 agent according to the disclosure is administered at an appropriate time interval of every 2 days, or every 4 days, or every week or biweekly or once every three weeks or once every month by monitoring one or more symptoms of a subject’s disease or disorder. Alternative, the ENPP1 agent may be administered at a total dose of 2.4 mg of ENPP1 polypeptide per mg of bodyweight of infant to achieve a constant level of enzymatic activity of ENPP1. The ENPP1 polypeptide can be dosed once a week by a single administration, once a week, at 2.4 mg / kg dosage. Alternately, 1.2 mg / kg of ENPP1 polypeptide can be twice per week, resulting in a total weekly dose of 2.4 mg / kg. Another option is to administer 0.8 mg / kg three times per week, which also adds up to 2.4 mg / kg per week. Alternatively, the dose can be divided into 0.6 mg / kg given four times per week, or 0.4 mg / kg administered six times per week—both of which achieve the same total weekly dose of 2.4 mg / kg. These flexible dosing strategies allow healthcare providers to tailor treatment plans to the specific needs of each infant while maintaining consistent therapeutic exposure to the ENPP1 polypeptide. Without wishing to be bound by theory, it is believed that maintaining a steady state concentration of plasma PPi at normal levels reduces and / or prevents progression of pathological calcification of subjects. In certain embodiments, the polypeptide is administered locally, regionally, parenterally or systemically to the subject. In some embodiments, the polypeptide is administered subcutaneously. As used herein, “parenteral administration” of a formulation includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the ENPP1 agent through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of an ENPP1 agent by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques. The regimen of administration may affect what constitutes an effective amount. For example, several divided dosages, as well as staggered dosages may be administered in a given time period (daily) or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, selection of a recited dose of an ENPP1 agent may be indicated by the exigencies of the therapeutic or prophylactic situation. Atty. Docket No.4427-12602 Administration of the compositions of the present disclosure (e.g., soluble ENPP1 polypeptides and fusion proteins thereof) to a patient, such as a mammal (i.e., a human), may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder in the patient. An effective amount of the recited dosages of an ENPP1 agent necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. A selected dosage is determined based on the biological activity of the therapeutic compound which in turn depends on the half-life and the area under the plasma time of the therapeutic compound curve. Syringe Compositions The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 2.4 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 1.8 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 1.2 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 0.8 mg of ENPP1 polypeptide per Atty. Docket No.4427-12602 kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 0.6 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 0.4 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. The present disclosure provides a pre-filled syringe comprising a pharmaceutical composition containing a therapeutically effective amount of ENPP1 polypeptide for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The syringe is configured to deliver a dose of 0.2 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical composition is formulated in a sterile, buffered aqueous solution suitable for parenteral administration. In some embodiments, the pharmaceutical composition further comprises approximately 20 mM citrate buffer at pH 6.3, approximately 2 mM calcium chloride, approximately 175 mM sucrose, approximately 82 mM (D)-mannitol, and approximately 0.05% w / v polysorbate 20. In alternative formulations, the composition comprises approximately 8 mM citrate at pH 6.3, approximately 0.8 mM calcium chloride, approximately 70 mM sucrose, approximately 32 mM (D)-mannitol, and approximately 0.02% w / v polysorbate 20. These excipients are selected to enhance the stability, solubility, and bioavailability of the ENPP1 polypeptide, while maintaining isotonicity and minimizing aggregation or degradation during storage and administration. The syringe may be constructed from medical-grade polymer or glass and may include a fixed or detachable needle. It may be designed as a single-use, sterile, and optionally safety- engineered device to prevent needlestick injuries. The syringe may be pre-calibrated or marked to correspond to the appropriate volume based on the infant’s weight, facilitating accurate and reproducible dosing in clinical or home settings. The pre-filled syringe format ensures ease of use, reduces preparation time, and minimizes dosing errors, thereby supporting safe and effective delivery of ENPP1 polypeptide therapy in pediatric patients. Atty. Docket No.4427-12602 The disclosure further provides methods of administering ENPP1 polypeptide such as INZ-701 using the pre-filled syringe to achieve a total weekly dose of 2.4 mg / kg. This total dose may be delivered through various dosing regimens, including: 1.2 mg / kg administered twice weekly; 0.8 mg / kg administered three times weekly; 0.6 mg / kg administered four times weekly; or 0.4 mg / kg administered six times weekly. These flexible dosing strategies allow clinicians to tailor treatment to the individual needs of the infant while ensuring consistent therapeutic exposure and efficacy. Vial Compositions The present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of ENPP1 polypeptide, provided in a vial for use in the treatment of pathological calcification disorders, such as Generalized Arterial Calcification of Infancy (GACI). The composition is intended to be administered at a dose of 2.4 mg of ENPP1 polypeptide per kilogram of the infant’s body weight. The pharmaceutical formulation is supplied in a sterile, sealed vial suitable for parenteral administration following reconstitution or dilution, if necessary. In some embodiments, the vial comprises a pharmaceutical composition comprising ENPP1 polypeptide such as INZ-701 at concentrations ranging from 1 mg / ml to 200 mg / ml which gets diluted to achieve a therapeutic dose of ENPP1 polypeptide ranging from 0.2 mg / kg to 2.4 mg / kg for administration to an infant having pathological calcification. In some embodiments, the pharmaceutical composition comprises approximately 20 mM citrate buffer at pH 6.3, approximately 2 mM calcium chloride, approximately 175 mM sucrose, approximately 82 mM (D)-mannitol, and approximately 0.05% w / v polysorbate 20. In alternative formulations, the composition comprises approximately 8 mM citrate at pH 6.3, approximately 0.8 mM calcium chloride, approximately 70 mM sucrose, approximately 32 mM (D)-mannitol, and approximately 0.02% w / v polysorbate 20. These excipients are selected to optimize the stability, solubility, and bioavailability of the ENPP1 polypeptide, while maintaining isotonicity and minimizing aggregation or degradation during storage and administration. The vial may be constructed from medical-grade glass or polymer and is designed to maintain sterility and chemical stability over the intended shelf life. The vial may be single-use or multi-dose, and may be stored under refrigerated conditions. The composition may be withdrawn using a sterile syringe and administered via subcutaneous or intravenous injection, depending on clinical requirements. The disclosure further provides methods of administering ENPP1 polypeptide using the vial-based formulation to achieve a total weekly dose of 2.4 mg / kg of bodyweight of an infant having pathological calcification or GACI or ENPP1 deficiency. This total dose may be Atty. Docket No.4427-12602 delivered through various dosing regimens, including: 1.2 mg / kg administered twice weekly; 0.8 mg / kg administered three times weekly; 0.6 mg / kg administered four times weekly; or 0.4 mg / kg administered six times weekly. These flexible dosing strategies allow clinicians to tailor treatment to the individual needs of the infant while ensuring consistent therapeutic exposure and efficacy. 13. Prophylactic Administration Armed with the disclosure herein, one skilled in the art would thus appreciate that the prevention of a disease or disorder in a subject encompasses administering to a subject an ENPP1 polypeptide as a preventative measure against the disease or disorder. The relative amounts of the active ingredient (e.g., soluble ENPP1 polypeptides and fusion proteins thereof), the pharmaceutically acceptable carrier, and any additional ingredients in a formulation disclosed herein will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between about 0.1% and about 100% (w / w) active ingredient. 14. Diseases Relating to Low PPi In some embodiments, the disclosure contemplates methods of reducing or preventing progression of diseases caused by lower levels of plasma PPi in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polypeptides disclosed herein to increase the plasma PPi of the subjects to normal (1-3 µM) or above (30-50% higher than) normal levels and then to maintain the plasma PPi at a constant normal or above normal level thereafter. The method further comprises administering additional therapeutic effective amounts at intervals of two days, three days, one week or one month in order to maintain the Plasma PPi of the subject at a constant normal or above normal level to reduce or prevent the progression of pathological calcification or ossification. In certain embodiments, a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein can be used to raise pyrophosphate (PPi) levels in a subject having PPi level lower than normal level (the median of normal PPi range is around 2µM). In other embodiments, a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein can be used to reduce or prevent progression of pathological calcification or ossification in a subject having PPi levels lower than normal level. In some embodiments, a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein can be used to treat ENPP1 deficiency (e.g., GACI and ARHR2) manifested by a reduction of extracellular PPi concentration in a subject. In certain embodiments, the steady state level of plasma PPi achieved after administration of a first dosage of a soluble ENPP1 polypeptide or ENPP1 fusion Atty. Docket No.4427-12602 polypeptide disclosed herein is maintained for a time period of at least 2 days, at least 4 days, at least a week or at least a month. In some embodiments, the disclosure contemplates methods of reducing or preventing progression of a disease caused by lower than normal levels of plasma PPi in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein (e.g., SEQ ID NOs: 3-5) to increase and / or sustain the plasma PPi of the subjects to a level that is about 90%, 95%, 100%, 105%, 110%, 120%, 130%, 140%, or 150% of the normal PPi level. In certain embodiments, the method further comprises further administration of the polypeptide disclosed herein every two days, three days, one week, or one month in order to maintain the plasma PPi levels at a level that is about 90%, 95%, 100%, 105%, 110%, 120%, 130%, 140%, or 150% of the normal PPi level, thus preventing the progression of pathological calcification or ossification. 15. Treatment / Indications The recited dosages of an ENPP1 agent disclosed herein may be used in methods of treating, reversing, or preventing progression of diseases associated with an ENPP1 deficiency or an ABCC6 deficiency as disclosed herein. In an aspect, the disclosure relates to administering to a subject having an ENPP1 deficiency or an ABCC6 deficiency, an ENPP1 agent at a total dose of about 2.4 mg of ENPP1 fusion polypeptide (ENPP1-Fc) per kilogram of body weight of the subject in order to restore a physiological level of ENPP1 in the plasma or tissues of the subject. In an aspect, the disclosure relates to administering to a subject having an ENPP1 deficiency or an ABCC6 deficiency, an ENPP1 agent at a total dose of about 2.4 mg of ENPP1 fusion polypeptide (ENPP1-Fc) per kilogram of body weight of the subject in order to restore a physiological level of Pi and / or PPi in the plasma of the subject. The physiological level of Pi and PPi in human serum (and in mammals generally) is 1-3 mM and 2-3 µM respectively. In an aspect, the disclosure relates to a method for preventing progression of or reducing vascular calcification in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: to thereby prevent the progression of or reduce vascular calcification in the subject, the method comprising: administering to the subject an ENPP1 agent at a total dose of about 2.4 mg of ENPP1 fusion polypeptide (ENPP1-Fc) per kg of body weight of the subject to thereby prevent the progression of or reduce vascular calcification in the subject. In an aspect, the disclosure relates to a method for preventing the progression of or reducing pathological calcification in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a total dose Atty. Docket No.4427-12602 of about 2.4 mg of ENPP1 fusion polypeptide (ENPP1-Fc) per kilogram of body weight of the subject to thereby prevent the progression of or reduce pathological calcification in the subject. The recited dosages of an ENPP1 agent disclosed herein may be used in methods of treating, reversing, or preventing progression of diseases associated with pathological calcification as disclosed herein. In an aspect, the disclosure relates to administering to a subject having pathological calcification an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject in order to restore a physiological level of ENPP1 in the plasma or tissues of the subject. In an aspect, the disclosure relates to administering to a subject having pathological calcification an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject in order to restore a physiological level of Pi and / or PPi in the plasma of the subject. The physiological level of Pi and PPi in human serum (and in mammals generally) is 1-3 mM and 1-3 µM respectively. In an aspect, the disclosure relates to a method for preventing progression of or reducing vascular calcification in a subject, the method comprising: to thereby prevent the progression of or reduce vascular calcification in the subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce vascular calcification in the subject. In an aspect, the disclosure relates to a method for preventing the progression of or reducing pathological calcification in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce pathological calcification in the subject. In an aspect, the disclosure relates to a method for preventing the progression of or reducing tissue calcification in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. In an aspect, the disclosure relates to a method for preventing the progression of or reducing pathological ossification in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. In an aspect, the disclosure relates to a method for preventing the progression of or reducing tissue calcification in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. Atty. Docket No.4427-12602 In an aspect, the disclosure relates to a method for preventing the progression of or reducing pathological ossification in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. In an aspect, the disclosure relates to a method for increasing circulating pyrophosphate (PPi) in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby increase circulating PPi in the subject. In an aspect, the disclosure relates to a method for increasing pyrophosphatase activity in a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby increase circulating PPi in the subject. In an aspect, the disclosure relates to a method for ameliorating one or more symptoms of ENPP1 Deficiency or ABCC6 deficiency in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby ameliorate one or more symptoms of ENPP1 Deficiency or one or more symptoms of ABCC6 deficiency in the subject. In an aspect, the disclosure relates to a method for treating a subject with ENPP1 Deficiency or with ABCC6 deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of body weight of the subject to thereby treat the subject. In certain aspects, the present disclosure relates to the use of an ENPP1 agent, such as a polypeptide having amino acid sequences as set forth in, e.g., SEQ ID NOs: 2, 3, 4, and 5. In some embodiments, the pathological calcification is selected from the group consisting of kidney and bladder stones, dental pulp stones, gall stones, salivary gland stones, chronic calculous prostatitis, testicular microliths, calcification in hemodialysis patients, atherosclerosis, malacoplakia, scleroderma (systemic sclerosis), calcinosis cutis, calcific aortic stenosis, calcific tendonitis, synovitis and arthritis, diffuse interstitial skeletal hyperostosis, juvenile dermatomyositis, Generalized Arterial Calcification of Infancy (GACI), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, autosomal hypophosphatemic rickets (ARHR2), osteoarthritis, calcification of atherosclerotic plaques, Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), Pseudoxanthoma elasticum (PXE), ankylosing spondylitis, hardening of the arteries, calciphylaxis, and systemic lupus erythematosus. Atty. Docket No.4427-12602 In some embodiments, the pathological calcification is selected from the group consisting of Pseudoxanthoma elasticum (PXE) and calcification of atherosclerotic plaques. In some embodiments, the pathological calcification is selected from the group consisting of idiopathic infantile arterial calcification (IIAC) and calcification of atherosclerotic plaques. In some embodiments, the disclosure contemplates methods of reducing or preventing progression of ectopic calcification of soft tissue, including reducing, ameliorating, or preventing vascular calcification, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein. In some embodiments, the disclosure contemplates methods of reducing or preventing progression of diseases caused by an ENPP1 deficiency (e.g., GACI and ARHR2), the method comprising administering to the subject a therapeutically effective amount of a soluble ENPP1 polypeptide or ENPP1 fusion protein disclosed herein (e.g., SEQ ID NOs: 2, 3, 4, and 5). In some embodiments, the ENPP1 deficiency is GACI. In some embodiments, the ENPP1 deficiency is ARHR2. In some embodiments, the disclosure contemplates methods of reducing or preventing progression of diseases caused by an ABCC6 deficiency (e.g., PXE), the method comprising administering to the subject a therapeutically effective amount of a soluble ENPP1 polypeptide or ENPP1 fusion protein disclosed herein (e.g., SEQ ID NOs: 2, 3, 4, and 5). In some embodiments, the ABCC6 deficiency is PXE. In some embodiments, subjects having ABCC6 deficiency exhibit symptoms similar to a person diagnosed with GACI or ARHR2. In some embodiments, the disclosure contemplates methods of reducing or preventing progression of diseases caused by pathological calcification (e.g., GACI and ARHR2), the method comprising administering to the subject a therapeutically effective amount of a soluble ENPP1 polypeptide or ENPP1 fusion protein disclosed herein (e.g., SEQ ID NOs: 2, 9, 10, and 11). In some embodiments, the subject exhibiting pathological calcification has ENPP1 deficiency. In some embodiments subject exhibiting pathological calcification has ABCC6 deficiency. In some embodiments, the polypeptide is a secreted product of an ENPP1 precursor protein expressed in a mammalian cell. In other embodiments, the ENPP1 precursor protein comprises a signal peptide sequence and an ENPP1 polypeptide, wherein the ENPP1 precursor protein undergoes proteolytic processing to the polypeptide disclosed herein. In some embodiments, in the ENPP1 precursor protein the signal peptide sequence is conjugated to the ENPP1 polypeptide N-terminus. Upon proteolysis, the signal sequence is cleaved from the ENPP1 precursor protein to provide the ENPP1 polypeptide. In certain embodiments, the signal peptide sequence is selected from the group consisting of ENPP1 signal peptide sequence, Atty. Docket No.4427-12602 ENPP2 signal peptide sequence, ENPP7 signal peptide sequence, and ENPP5 signal peptide sequence. It will be appreciated by one of skill in the art, when armed with the present disclosure including the methods detailed herein, that the disclosure is not limited to treatment of a disease or disorder once it is established. Particularly, the symptoms of the disease or disorder need not have manifested to the point of detriment to the subject; indeed, the disease or disorder need not be detected in a subject before treatment is administered. That is, significant pathology from disease or disorder does not have to occur before the present ENPP1 polypeptides may provide benefit. In certain aspects, the disclosure relates to methods for preventing diseases and disorders in a subject, in that a soluble ENPP1 polypeptide or ENPP1 fusion polypeptide disclosed herein can be administered to a subject prior to the onset of the disease or disorder, thereby preventing the disease or disorder from developing. Therefore, the disclosure relates to methods for preventing or delaying onset, or reducing progression or growth, of a disease or disorder in a subject, comprising administering an ENPP1 polypeptide to a subject prior to detection of the disease or disorder. In certain embodiments, the ENPP1 polypeptide is administered to a subject with a strong family history of the disease or disorder, thereby preventing or delaying onset or progression of the disease or disorder. 16. ENPP1 Polypeptide Sequences Table 1: Sequences Atty. Docket No.4427-12602 Atty. Docket No.4427-12602 Atty. Docket No.4427-12602 SEQ ID NO: 7 (Mouse NPP1- NCBI accession NP_001295256.1) 1 MERDGDQAGH GPRHGSAGNG RELESPAAAS LLAPMDLGEE PLEKAERARP AKDPNTYKVL 61 SLVLSVCVLT TILGCIFGLK PSCAKEVKSC KGRCFERTFS NCRCDAACVS LGNCCLDFQE 121 TCVEPTHIWT CNKFRCGEKR LSRFVCSCAD DCKTHNDCCI NYSSVCQDKK SWVEETCESI 181 DTPECPAEFE SPPTLLFSLD GFRAEYLHTW GGLLPVISKL KNCGTYTKNM RPMYPTKTFP 241 NHYSIVTGLY PESHGIIDNK MYDPKMNASF SLKSKEKFNP LWYKGQPIWV TANHQEVKSG 301 TYFWPGSDVE IDGILPDIYK VYNGSVPFEE RILAVLEWLQ LPSHERPHFY TLYLEEPDSS 361 GHSHGPVSSE VIKALQKVDR LVGMLMDGLK DLGLDKCLNL ILISDHGMEQ GSCKKYVYLN 421 KYLGDVNNVK VVYGPAARLR PTDVPETYYS FNYEALAKNL SCREPNQHFR PYLKPFLPKR 481 LHFAKSDRIE PLTFYLDPQW QLALNPSERK YCGSGFHGSD NLFSNMQALF IGYGPAFKHG 541 AEVDSFENIE VYNLMCDLLG LIPAPNNGSH GSLNHLLKKP IYNPSHPKEE GFLSQCPIKS 601 TSNDLGCTCD PWIVPIKDFE KQLNLTTEDV DDIYHMTVPY GRPRILLKQH RVCLLQQQQF 661 LTGYSLDLLM PLWASYTFLS NDQFSRDDFS NCLYQDLRIP LSPVHKCSYY KSNSKLSYGF 721 LTPPRLNRVS NHIYSEALLT SNIVPMYQSF QVIWHYLHDT LLQRYAHERN GINVVSGPVF 781 DFDYDGRYDS LEILKQNSRV IRSQEILIPT HFFIVLTSCK QLSETPLECS ALESSAYILP 841 HRPDNIESCT HGKRESSWVE ELLTLHRARV TDVELITGLS FYQDRQESVS ELLRLKTHLP 901 IFSQED SEQ ID NO: 8 (Cow NPP1- NCBI accession NP_001193141.1) 1 MERDSCAGGG SRGGEGGRGP REGLAGNGRD PGPGRAAEAS GEPQAAASLL APMDLGEEPL 61 ERAARARPAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS CAKEIKSCKG RCFERTFGNC 121 RCDAACVDLG NCCLDYQETC IEPERIWTCT KFRCGEKRLS RSLCSCSDDC KDKGDCCINH 181 GSVCRGEKSW AEEECDSIDE PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKT 241 CGTYTKNMRP VYPTKTFPNH YSIVTGLYPE SHGIIDNNIY DPQMNANFAL KNKEKFNPEW 301 YKGEPIWLTA KYQGLKTGTF FWPGSDVKIN GIFPDIYKIY NVSVPFEERI LAILKWLQLP 361 KDERPHFYTL YLEEPDSSGH SYGPVSSEVI RALQRVDNMV GMLMDGLKEL NLHRCLNLIL 421 ISDHGMEQGS CKKYVYLNKY LGDTKDYKVV YGPAARLRPS DVPDKYYSFD YEGIAKNLSC 481 QEPNQHFKPY LKHFLPKRLH FAKNDRIERL TFYLDPQWQL ALNPSERKYC GGGFHGSDNT 541 FLNMQALFIG YGPGFKHSTE VDSFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLSNPVY 601 TPKHPKEVRP LVQCPFTRAP RESLDCSCDP SILPIVDFQT QLNLTMAEEK TIKRGALPYG 661 RPRVLQNSTV CLLYQHQFVS GYSRDILMPL WTSYTIGRND SFSTEDFSNC LYQDLRIPLS Atty. Docket No.4427-12602 721 PVHKCSFYKN NAKLSYGLLS PPQLHKGSSQ VYSEALLTTN IVPMYQSFQV IWHYLHGTLL 781 QRYAEERNGL NVVSGPVFDS DYDGRYDSLE TLKQNSKIIR NLEVLIPTHF FLVLTSCKNT 841 SQTPLQCENL DAMAFILPHK TDNSESCAHG KHESLWVEEL LKLHTARITD VEHITGLSFY 901 QERKEPISDI LKLKTHLPTF NQED SEQ ID NO: 9 (Rabbit NPP1- NCBI accession NP_001162404.1) 1 MERDGCAGGG SRGGEGGRAP REGPAGNSRD PGRSHAAEAP GNPQAAASLL APMDVGEEPL 61 EKAARARTAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS CAKEVKSCKG RCFERTFGNC 121 RCDAACVELG NCCLDYQETC IEPEHIWTCN KFRCGEKRLT RSLCACSDDC KDQGDCCINY 181 SSVCQGEKSW VEEPCESINE PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKK 241 CGTYTKNMRP VYPTKTFPNH YSIVTGLYPE SHGIIDNKMY DPKMNASFSL KSKEKFNPEW 301 YKGEPIWVTA KYQGLKSGTF FWPGSDVEIN GIFPDIYKMY NGSVPFEERI LAVLQWLQLP 361 KDERPHFYTL YLEEPDSSGH SYGPVSSEVI KALQRVDNMV GMLMDGLKEL NLHRCLNLIL 421 VSDHGMEQGS CKKYIYLNKY LGDVKNIKVI YGPAARLRPS DVPDKYYSFN YEGIARNLSC 481 REPNQHFKPY LKHFLPKRLH FAKSDRIEPL TFYLDPQWQL ALNPSERKYC GSGFHGSDNI 541 FSNMQALFVG YGPGFKHGIE VDTFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLKNPVY 601 TPKHPKEVHP LIQCPFTRNP RDNLGCSCNP SILPIEDFQT QFNLTVAEEK NIKHETLPYG 661 RPRVLQKKNT ICLLSQHQFM SGYSQDILMP LWTSYTVDRN DSFSTEDFSN CLYQDFRISL 721 SPVHKCSFYK NNTKVSYGFL SPPQLNKNSR GIYSEALLTT NIVPMYQSFQ VIWRYFHDTL 781 LRKYAEERNG VNVVSGPVFD FDYDGRYDSL EILRQKRRVI RNQEILIPTH FFIVLTSCKD 841 ASQTPLHCEN LDTLAFILPH RTDNSESCLH GKHESSWVEE LLMLHRARIT DVEHITGLSF 901 YQQRKEPVSD ILKLKTHLPT FSQED SEQ ID NO: 10 (Baboon NPP1- NCBI accession NP_001076211.2) 1 MERDGCAGGG SQGGGKGGRG PREGLAGNGR DPSHGQASEA PGDPQAAASL LAPMDLGEEP 61 LEKAAGARPA KDPNTYKVLS LVLSVCVLTT ILGCIFGLKP SCAKEVKSCK GRCFERTFGN 121 CRCDVACVDL GNCCLDYQET CIEPERIWTC NKFRCGEKRL SRSLCACSDD CKERGDCCIN 181 YSAVCQGEKS WVEETCENIN EPQCPEGFEM PPTLLFSLDG FRAEYLHTWG GLLPVISKLK 241 KCGTYAKNMR PVYPTKTFPN HYSIVTGLYP ESHGIIDNKM YDPKMNASFS LKSKEKFNPE 301 WYKGEPIWLT AKYQGLRSGT FFWPGSDVKI NGIFPDIYKI YNGSVPFEER ILAILKWLRL 361 PKDERPHFYT LYLEEPDSSG HSYGPVSSEV IKALQRVDNM VGMLMDGLKE LNLHQCLNLI 421 LISDHGMEQG SCKKYIYLNK YLGDTKNIKV IYGPAARLRP SDVPEKYYSF NYENIARNLS 481 CREPNQHFKP YLKHFLPKRL HFAKSDRIEP LTFYLDPQWQ LALSPSERKY CGSGFHGSDN 541 VFSNMQALFV GYGPGFQHGI EVDSFENIEV YNLMCDLLNL TPAPNNGTHG SLNHLLKNPI 601 YTPKHPKEVQ PSVQCPLAGS PRDSLGCSCN PSILPIVDFQ TQFNLTTAEE KNINRASLPY 661 GRPRLLQKKS SVCLLYQHQF VSGYSHDVLM PLWTSYTVNR NDSFSTEDFS NCLYQDLRIS 721 FSPIHNCSFY KNNAKLSYGF LSPPQLSKDS SQIYSEALLT SNIVPMYQSF QVIWRYFHDT 781 LLQRYAEERN SINVVSGPVF DSDYDGRYDS SEALKRNRRV IRNQEILIPT HFFIVITSCK 841 NTSQTPLQCD NLDPLAFILP HRSDNSESCV HEKRESSWIE ELLMMHRARI MDVEHITGLS Atty. Docket No.4427-12602 901 FYQERKEPVS DILKLKTHLP TVSQED 17. Treatment Protocols The following protocols may be used as guidance for ENPP1 enzyme replacement therapy at the recited dosages of the ENPP1 agent, as determined to be appropriate by the medical practitioner. Treatment protocols set forth herein rely on the use of abbreviated terms, whose full names are set forth in glossary at Table 9. Arms and Interventions Study Design ^ Study Type: Interventional ^ Primary Purpose: Treatment ^ Study Phase: Phase 3 ^ The study is a multicenter, single-arm, open-label Phase 3 study to assess the efficacy and safety of ENPP1 agent such as ENPP1-Fc in infants with ENPP1 Deficiency. ^ Number of Arms: 1 ^ Masking: None (Open Label) ^ Size – 12 subjects Infants aged 0 to <1 year with a confirmed postnatal molecular diagnosis of ENPP1 Deficiency (i.e., homozygous or compound heterozygous biallelic ENPP1 mutations) are eligible to participate if all other eligibility criteria are met. Patients who have been treated with ENPP1 agent such as ENPP1-Fc as part of the Expanded Access Program (EAP) may be eligible to enroll if they meet all the enrollment criteria. Atty. Docket No.4427-12602 The study will consist of a Screening Period of up to 60 days, a Treatment Period of 52 weeks, a 52-week Extension Period, and an End of Treatment (EOT) Visit 30 days after the last dose of ENPP1 agent such as ENPP1-Fc. Study participants will receive ENPP1 agent such as ENPP1-Fc once weekly via subcutaneous (SC) injection. The first 5 doses will be administered in the clinic. Administration of ENPP1 agent such as ENPP1-Fc for all participants will continue in the clinic until the Investigator determines that the study participant may transition to offsite administration (e.g., in the home setting). Upon transitioning to offsite administration, the Investigator or designee will contact the caregiver(s) / healthcare provider(s) at least weekly for the first 4 weeks to assess safety and dosing compliance. Thereafter, the Investigator will determine the frequency of contact with the caregiver(s) / healthcare provider(s) based on compliance, wellbeing of the study participant, clinical judgment, and in accordance with institutional and local guidelines. On in-clinic days when blood sampling is performed for PPi, study participants may not be dosed until it is confirmed that their pre-dose PPi and immunogenicity (if applicable) samples have been successfully collected and processed. The PPi measurements taken at Screening and pre-dose on Day 1 will be used for determination of Baseline PPi. Study participants who discontinue treatment will continue to be followed for their ongoing disposition for survival outcome at least quarterly, through the end of the study. Eligibility and Prohibited Medication or Therapy Eligibility Criterion 1. Minimum Age: 0 day (i.e. from birth) 2. Maximum Age: Under 1 Year (or 12 months) 3. Sex: All 4. Gender Based: No 5. Accepts Healthy Volunteers: No Inclusion Criteria Study participants must meet all of the following inclusion criteria: 1. Caregiver(s) written or electronic consent after the nature of the study has been explained, and prior to any research-related procedures, per International Council on Harmonisation (ICH) Good Clinical Practice (GCP). 2. A confirmed postnatal molecular genetic diagnosis of ENPP1 Deficiency with biallelic mutations (i.e., homozygous or compound heterozygous) performed using assays that meet CE- marked requirements, or by a College of American Pathologists / Clinical Laboratory Improvement Amendments (CAP / CLIA) certified laboratory, or a regional equivalent. Atty. Docket No.4427-12602 3. Clinical evidence of GACI, which may include pathologic ectopic calcification, heart failure, respiratory distress, edema, cyanosis, hypertension, cardiomegaly or other manifestations. 4. Males and females from birth to <1 year of age at Study Day 1. 5. Plasma PPi concentration of <1400 nM: a. At study Screening if study participant has not participated in the EAP. b. At the documented baseline prior to treatment with ENPP1 agent such as ENPP1-Fc in the expanded access program (EAP). 6. Body weight ≥0.5 kg at the time of the first dose of ENPP1 agents such as ENPP1-Fc. 7. Be able to complete all aspects of the study in the opinion of the Investigator. 8. Caregiver(s) agree to provide access to their infant’s relevant medical records. Exclusion Criteria Individuals who meet any of the following exclusion criteria will not be eligible to participate: 1. In the opinion of the Investigator, presence of any clinically significant disease or laboratory abnormality not associated with ENPP1 Deficiency that will preclude study participation and / or may confound interpretation of study results. 2. Care has been withdrawn or infant is receiving end of life or hospice care 3. Planned surgery that may confound the interpretation of study results during the 52- week Treatment Period in the opinion of the Investigator 4. Known intolerance to ENPP1 agent such as ENPP1-Fc or any of its excipients 5. Previous treatment with ENPP1 agent such as ENPP1-Fc unless prior treatment was part of the EAP, in which case they may participate upon Sponsor approval 6. Concurrent participation in another interventional clinical study and / or has received an investigational drug within 5 half-lives or within 4 weeks prior to the first dose of ENPP1 agent such as ENPP1-Fc, whichever is longer, or use of an investigational device In infants who suffer from ENPP1 Deficiency, an acutely life-threatening phenotypic presentation can result, in which there is generalized arterial calcification and ultimately a high rate of mortality. Mortality is at the highest during infancy (ranging from 41% to 70%) and occurs predominantly in the first 6 months of life. Atty. Docket No.4427-12602 Estimated Duration of Study Participation Study participation consists of a Screening Period of up to 60 days, a 52-week Treatment Period, a 52-week Extension Period, and an EOT Visit 30 days after the last dose of ENPP1 agent such as ENPP1-Fc. Objectives and Endpoints Atty. Docket No.4427-12602 Atty. Docket No.4427-12602 Prohibited Medications Use of bisphosphonates prior to and during the study is permitted if initiated prior to Screening. Initiation of bisphosphonates any time during the study from the time of the first dose of ENPP1-Fc is prohibited. Statistical Considerations The analysis of PPi will be based on a change from Baseline approach. The analysis of survival will be based on a comparison to a historical control dataset, with patients matched to the study participants. Survival will be calculated from day of birth. The primary survival analysis will be based on all-cause mortality. A sub-analysis of study participants from the EAP will be conducted. A full description of the statistical evaluations, general considerations, and procedures for handling missing data will be provided in the SAP. Screening Following written informed consent and applicable assent, study participants will undergo Screening assessments and be evaluated for eligibility according to the inclusion and exclusion criteria. The Screening Period will last up to 60 days. Screening assessments to determine eligibility may be completed over several days and should be conducted in a manner and order to minimize study participant burden. Screening assessments must be completed after informed consent is obtained and prior to administration of first dose of ENPP1-Fc unless otherwise specified in this protocol. A unique identification (ID) number will be assigned to each study participant at the time of Screening. If a study participant does not meet any of the eligibility criteria, Screening will stop and the reason for screen failure will be documented in the study participant’s source records and in the clinical database. The following assessments will be performed during Screening: ^ Medical history (including confirmation of postnatal genetic testing for the ENPP1 mutation, which will be conducted outside of the clinical study), prior medications, demographics, and disease history: Will be collected at Screening including disease history, clinical and genetic diagnosis, medications taken within the past 60 days, all active conditions and any past condition considered to be relevant to ENPP1 Deficiency by the Investigator. Disease history will include previous history of GACI. Available family history will be noted, including any available previous mutation analysis results from relevant family members with Atty. Docket No.4427-12602 appropriate inheritance patterns. Demographic information, including age, date of birth, sex, ethnicity, and race, will be collected as permitted by local regulations. ^ Growth measurements: will be collected during Screening to determine Baseline. ^ Plasma PPi concentration: For study participants who did not participate in the EAP, 2 separate samples will be measured for determination of Baseline, one sample taken at Screening to determine eligibility (i.e., PPi <1400 nM) and another sample at pre-dose on Day 1. For study participants from the EAP, their Baseline is the documented PPi concentration prior to treatment with ENPP1-Fc in the EAP; a screening assessment is not needed. ^ Chest CT scan: Will be conducted during Screening to determine Baseline. ^ Bayley-3: Will be performed if applicable and if scales (or applicable translations) are available at the time of enrollment. ^ Safety assessments: Will include physical examination, vital signs, ECG, echocardiogram, and clinical laboratory evaluations. Monitoring of AEs and concomitant medications will start after the ICF is signed. Repeat Screening Assessments and Rescreening Assessments not meeting the eligibility criteria may be retested within the 60-day screening window. If a study participant does not meet eligibility criteria, they may be rescreened up to 2 times after consultation with the Sponsor for transient abnormalities or if the Investigator believes there has been a change in eligibility status. The Investigator will consult with the Sponsor to determine which of the screening procedures must be repeated to determine eligibility and / or establish Baseline. Study participants’ caregiver(s) must sign a new ICF prior to rescreening and will be assigned a new study identification number. No exceptions to eligibility criteria (i.e., protocol waivers) will be granted. Study participants must be dosed within 60 days from the start of Screening (day of consent). Efficacy Assessments Assessments to evaluate efficacy endpoints are described below and will be conducted according to the time points indicated in Table 2 and Table 3. Table 4 shows post treatment follow up and end of study schedule. Atty. Docket No.4427-12602 Table 2: Schedule of Events Note: Results of assessments done for the clinical management of the study participant that align with protocol specifications may be used for study purposes. If the same assessment is performed multiple times, the assessment closest to the protocol time point will be used. A PK / PD sampling scheduled is presented in Table 3. The post-treatment follow-up and end of study schedule is presented in Table 4. Note: When a time point for vital signs, physical examination & growth measures, ECG, blood draws, imaging (echocardiogram / CT scan), and Bayley-3 coincide, procedures should be carried out in said order if feasible. Atty. Docket No.4427-12602 a. Screening Period: Assessments not meeting eligibility criteria may be repeated within the 60-day Screening window. If a potential study participant does not meet eligibility criteria for any reason, the participant may be retested or rescreened up to 2 times. b. Medical History: Review of confirmation of postnatal genetic testing for the ENPP] mutation, which will be conducted outside of the clinical study, performed using assays that meet CE-marked requirements, or by a CAP / CLIA certified laboratory, or regional equivalent. c. Growth Measurements: Body weight and length will be obtained at all indicated visits. The most recent body weight measurement (in kg) recorded will be used to calculate the dose to be administered until the next weight measurement is obtained. d. Body Weight: Only body weight will be measured at Days 15 and 22 for calculation of weight-adjusted dose; length will not be measured. e. Vital Signs: Vital signs assessed include systolic and diastolic blood pressure, heart rate, respiration rate, oxygen saturation, and temperature. For the first 5 doses, vital signs will be collected within 30 mins pre-dose and 1 hour post-dose (±15 mins). Additionally, on Day 1, vital signs will be collected post-dose hourly (±15 mins) through 6 hours post-dose. After the first 5 doses, vital signs will be collected within 30 minutes pre-dose and at a minimum, 1 hour (±15 minutes) post-dose at each in-clinic visit and / or home healthcare visit where dosing occurs. At each non-dosing in-clinic visit, vital signs will be collected within 30 minutes prior to blood sampling. If a study participant is hospitalized, their vital signs will be collected daily at a minimum. f. Total Blood Volume: Clinical Laboratory Evaluations analytes are provided in Appendix A. The total blood volume collected should not exceed 5% of the study participant’s total blood volume over a single visit, or 10% of their total blood volume over an 8-week period. See Section 8.1 for details on blood collection volumes for the EU and non-EU participants. g. Clinical Care Blood Samples: Blood draws performed as part of study participant’s clinical care may be used for protocol-required safety laboratory evaluations. When feasible, leftover blood samples acquired as part of the study participant’s clinical care will be retained for immunogenicity, PK, or biomarker assessments. h. Baseline Clinical Laboratory Evaluations and Urine Analysis: Baseline (Day 1) samples may be collected within 7 days prior to dosing on Day 1. i. Urine Analysis: Urine will be collected as feasible. Urine analysis analytes are provided in Appendix A. Atty. Docket No.4427-12602 j. Blood Samples and ECG: Blood samples and ECGs will be collected pre-dose at all indicated time points unless otherwise specified (see Table 3 for sample collection schedule for PK and PPi). k. PPi Concentration: See Table 3 for PPi sample collection time points. Additional samples (outside of the time points specified) may be collected if clinically indicated per Investigator discretion or upon Sponsor request. Dosing on Day 1 may not commence until it is confirmed that Baseline PPi, PK, and immunogenicity samples (if applicable) have been successfully collected and processed according to the Laboratory Manual. All PPi samples will be collected in the morning and pre-prandial, if feasible. l. PPi Concentration at Screening: Patients from the EAP do not need PPi measured at Screening. See Section 8.3. m. Day 1 PPi: Sample may be collected within 7 days prior to dosing on Day 1, provided all other inclusion criteria have been met. n. ENPP1-Fc Concentration and ENPP1 Specific Activity: See Table 3 for PK sample collection time points. Additional samples (outside of the time points specified) may be collected if clinically indicated per Investigator discretion or upon Sponsor request. o. Baseline ENPP1-Fc Concentration and ENPP1 Specific Activity, Biomarkers, and Immunogenicity: Baseline (Day 1) samples may be collected within 30 days prior to dosing on Day 1. The single blood sample for CRIM may be collected any time prior to dosing on Day 1. p. Immunogenicity: Additional samples (outside of the time points specified) may be collected if clinically indicated per Investigator discretion or upon Sponsor request. q. ECG: If performed within 7 days of first dose it does not need to be repeated pre- dose on Day 1. r. ENPP1-Fc Administration: The first 5 doses of ENPP1-Fc must be administered in the clinic. Then administration of ENPP1-Fc may be transitioned to off site. If a dosing day and clinic visit coincide, dosing should be conducted at the clinic. The dose should be administered at approximately the same time of day on the same day each week (±2 days). Study participants will be observed for at least 6 hours in the clinic following administration of their first 5 doses of ENPP1-Fc. Thereafter, the Investigator will prescribe the required post-dose monitoring duration for each study participant, which will not be less than 1 hour. s. Echocardiogram, CT scan, and Bayley-3: These procedures can be collected pre- or post-dose at all indicated time points. Atty. Docket No.4427-12602 t. Screening Echocardiogram and Chest CT Scan: These procedures must be conducted within 30 days prior to Day 1. u. Chest CT Scan at EOT Visit: A participant must have a chest CT scan at the EOT Visit if they have not received a chest CT scan compliant with study requirements in the prior 12 weeks. v. Bayley-3 (Developmental and Functional Performance Test): Bayley-3 should be performed if applicable and if scales (or applicable translations) are available at the time of enrollment, at Investigator’s discretion. w. Dose Diary Review and Study Drug Accountability: Study drug accountability will be performed continuously throughout the study and review of the dose diary will be done continuously once offsite administration of ENPP1-Fc begins. x. Healthcare Resource Utilization: This will be recorded as the number of days spent by study participants in the hospital, number of days in an intensive care unit, and number of days using mechanical ventilation. Bayley-3=Bayley Scale of Infant and Toddler Development – Third Edition; CAP / CLIA=College of American Pathologists / Clinical Laboratory Improvement Amendments; CRIM=cross-reactive immunologic material; CT=computed tomography; ECG=electrocardiogram; ENPP1=ectonucleotide pyrophosphatase / phosphodiesterase 1; EOT=End of Treatment; EU = European Union; PK=pharmacokinetic(s); PPi=inorganic pyrophosphate; SC=subcutaneous; Q=every. Table 3: PK / PD Sampling Schedule Atty. Docket No.4427-12602 a. Pre-dose PK and PPi samples may be collected up to 1 hour prior to dosing. b. Baseline (pre-dose Day 1) PK samples may be collected within 30 days prior to dosing on Day 1. c. Pre-dose PPi samples should be collected before 12 noon local time. Day 1 pre-dose PPi maybe collected within 7 days prior to dosing, provided all other inclusion criteria have been met. ENPP1=ectonucleotide pyrophosphatase / phosphodiesterase 1; h=hours; PD=pharmacodynamic(s); PK=pharmacokinetic(s); PPi=inorganic pyrophosphate. Table 4: Post-Treatment Discontinuation Follow-up and End of Study Schedule a. Upon treatment discontinuation, study participants may continue to be followed for their ongoing disposition for survival outcome at least quarterly via a telephone call, if feasible through the end of the study. b. Required only for ongoing items at EOT. EOT=End of Treatment; Q=every Any imaging performed to assess vascular disease (e.g., ectopic calcification and / or stenosis) as part of the participants’ standard clinical care during the 52-week Treatment Period will be collected for analysis. Plasma PPi Concentration While a 60% increase from baseline in PPi was used to determine sample size (, preliminary data from clinical trials in adults with ENPP1 Deficiency demonstrated PPi changes from baseline ranging from approximately 100% to over 1000% following treatment with ENPP1-Fc, with all study participants achieving PPi plasma levels comparable to healthy volunteers. Restoring circulating PPi to physiologic levels in ENPP1 Deficiency has been shown Atty. Docket No.4427-12602 to prevent pathologic mineralization in nonclinical studies, suggesting a direct link to PPi and calcification in ENPP1 Deficiency. Blood samples for PPi measurement will be collected pre-dose in the morning (before 12 noon local time) at the indicated time points (see Table 2 and Table 3) and pre-prandial if feasible. The Day 1, pre-dose PPi sample may be collected within 7 days prior to dosing on Day 1, provided all other inclusion criteria have been met. On Day 1, PPi samples will also be collected at 6 hours (±30 minutes) post-dose. After Day 1, PPi will be collected within 1 hour prior to dosing in accordance with timepoints indicated in Table 2 and Table 3. On in-clinic days when PPi sampling is performed and dosing is done, study participants may not be dosed until it is confirmed that their pre-dose PPi and immunogenicity (if applicable) samples have been successfully collected and processed. Samples will be collected, processed, and shipped as outlined in the Laboratory Manual and analyzed at a central laboratory in accordance with applicable policies and procedures using a validated assay. Blood draws performed as part of study participant’s clinical care may be used for protocol required safety laboratory evaluations. When feasible, leftover blood samples performed as part of the participant’s clinical care will be retained for immunogenicity, PK, or biomarker assessments. The Investigator will consult with the Sponsor in advance to verify the appropriateness of the left-over samples. Samples not collected due to blood volume limitations will not be reported as protocol deviations. Maximum allowable blood sample volumes based on participant body weight are provided in Table 5. Table 5: Maximum Allowable Blood Sample Volumes For participants >1.5 kg to <2.5 kg, total blood volume may be estimated assuming 80-90 mL / kg body weight, in neonates, approximately 100 mL / kg body weight. Note: When routine health care requires significant blood sampling, these maximums may even be excessive. Atty. Docket No.4427-12602 The PPi measurements taken at Screening and pre-dose on Day 1 will be used for determination of Baseline PPi. For patients that were in the EAP, their Baseline PPi is the value obtained prior to the first dose in the EAP. Chest CT Chest CT scans using the lowest possible dose of radiation will be used to measure vascular calcification in the coronary artery at the time points indicated in Table 2. The Screening chest CT scan must be completed within 30 days prior to Day 1. Sedation should not be used in the performance of protocol-mandated CT scans. Growth Measurements Height (or body length) and weight are common anthropometric measurements used to assess growth. These measurements are often converted to Z-scores in medical research and practice, particularly in pediatrics (Martinez-Millana et al 2018). A Z-score represents the degree to which that particular measurement for that individual differs from the reference value in the general population. Z-scores have also been used for measurement of efficacy in clinical trials. For example, changes in height and weight measured by Z-score were used to assess the efficacy of STRENSIQ in another hereditary bone disease, juvenile onset HPP (Strensiq [package insert] Revised June 2020). Height or weight velocity is a variable derived from the measurement of height or weight at different times and represents the increase in height or weight during a fixed period. Bayley Scales of Infant and Toddler Development – Third Edition: Developmental and Functional Performance Outcome The Bayley Scales of Infant and Toddler Development – Third Edition (Bayley-3) is a standardized and norm-referenced instrument that assesses changes in gross motor, fine motor, cognitive development, and language. It is administered in infants and children starting at 1 month until 42 months of age. The Bayley-3 will be administered to assess changes in gross motor, fine motor, and cognitive development. Bayley-3 should be performed if applicable and if scales (or applicable translations) are available at the time of enrollment, at Investigator’s discretion. The Bayley-3 consists of a core battery of 5 scales, 3 of which are administered by a trained qualified professional with infant interaction experience, and 2 of which are parent reported. The administered scales include the following: Cognitive Scale, Language Scale (including the Receptive Communication and Expressive Communication subtests), and Motor Scale (including the Fine Motor and Gross Motor subtests). The Social-Emotional Scale and Adaptive Behavior Scale together form the Social-Emotional and Adaptive Behavior Questionnaire, which is completed by the caregiver(s). Atty. Docket No.4427-12602 The Language Scale will be administered only to native English speakers in English speaking countries. From raw scores, scaled scores, developmental age equivalents, and growth scores can be calculated for the Cognitive, Receptive Communication, Fine Motor, Expressive Communication, and Gross Motor subtests. Scaled scores also can be used to calculate the Cognitive, Language, and Motor composite scores, percentile ranks, and confidence intervals. The details of administration of the test and calculations are described in the Assessor’s Manual. If local regulations permit and with caregiver(s) consent, sites may record the administration of the developmental and / or functional performance outcome assessment on video. Videos will be sent to a representative of the Sponsor for removal of study participant identifiers. The Sponsor will only receive videos with study participant identifiers removed. The videos will be labeled with the study participant ID and date. Biomarkers In addition to low plasma PPi, ENPP1-deficient patients are characterized biochemically by low serum phosphate and high FGF23. Blood samples will be collected to measure the following biomarker levels at the time points indicated in Table 2: serum 1,25(OH)2D3, intact FGF23 in plasma, and serum phosphate. Baseline (Day 1) biomarker samples may be collected within 30 days prior to dosing on Day 1. Biomarker samples will be collected, processed, and shipped as outlined in the Laboratory Manual. If possible, samples will be collected at approximately the same time of day throughout the study to minimize intrasubject variability due to diurnal variation. Pharmacokinetic Evaluations Assessment of ENPP1-Fc PK (ENPP1-Fc plasma concentration and ENPP1 activity) is a secondary endpoint in this study. Baseline (Day 1) samples may be collected within 30 days prior to dosing on Day 1. Predose samples will be collected within 1 hour prior to dosing, and post-dose samples will be collected according to the Schedule of Events (Table 2 and Table 3). Samples for PK will be collected, processed, and shipped as outlined in the Laboratory Manual. PK samples will be taken pre-dose and pre-prandial where feasible. Samples will be analyzed for ENPP1-Fc concentration and ENPP1 activity to generate concentration-time profiles; bioanalyses will be performed at a central laboratory using validated assays. Details of the estimation of PK parameters is described below. Atty. Docket No.4427-12602 Safety Evaluations Adverse events (AE) are one of the outcome measures to assess safety and tolerability. Any changes in vital signs, weight, physical examination, and abnormal clinical laboratory parameters considered clinically significant by the Investigator will be reported as an AE. The assessments to measure the remaining safety endpoints are described below and will be conducted according to the time points indicated in Table 2. Echocardiogram Echocardiogram will be collected and used to assess heart function (including measurement of left ventricular ejection fraction), and to identify any other abnormalities, for example, calcification of heart valves. Sedation should not be used in the performance of protocol-mandated echocardiograms. If the investigator makes the determination that sedation is necessary to obtain an optimal echocardiogram, then either the echocardiogram will not be collected, or it will be accepted that a sub-optimal echocardiogram will be obtained without sedation. The Screening echocardiogram must be completed within 30 days prior to Day 1. Physical Examination A complete physical examination includes an assessment of systemic organ involvement and inspection of: ^ General appearance ^ Head, ears, eyes, nose, and throat ^ Neck ^ Skin ^ Cardiovascular system ^ Respiratory system ^ Gastrointestinal system ^ Nervous system Physical examinations must be performed by the Investigator or a medically qualified delegate. Any clinically significant abnormality identified during the physical examination conducted at screening will be recorded as a pre-existing condition (i.e., part of the medical history). Any changes in the physical examination that are considered clinically significant by the Investigator will be reported as an AE. Atty. Docket No.4427-12602 Vital Signs Vital signs assessed in this study include systolic blood pressure and diastolic blood pressure (mm Hg), heart rate (beats per minute), respiration rate (breaths per minute), oxygen saturation, and temperature (°C). Vital signs will be measured after the study participant has been at rest ≥5 minutes. Respiratory rate will be measured over at least 15 seconds and adjusted per minute. Body temperature can be measured using the most appropriate method for the age of the study participant using calibrated equipment. For the first 5 doses, vital signs will be collected within 30 minutes pre-dose and 1 hour post-dose (±15 mins). Additionally, on Day 1, vital signs will be collected post-dose hourly (±15 mins) through 6 hours post-dose. After the first 5 doses, vital signs will be collected within 30 minutes pre-dose and at a minimum, 1 hour (±15 minutes) post-dose at each in-clinic visit and / or home healthcare visit where dosing occurs. At each non-dosing in-clinic visit, vital signs will be collected within 30 minutes prior to blood sampling. If a study participant is hospitalized, their vital signs will be collected daily at a minimum. Additional measurements may be obtained as clinically indicated. Weight Measurements The study participant’s weight (in kilograms) will be obtained at each visit and will be measured using a calibrated scale. The weight obtained at Day 1 will be used to calculate the initial dose of ENPP1-Fc (in mg) to be administered on a mg / kg basis. The weight will be collected at indicated visits as indicated in Table 2. The most recent body weight measurement (in kg) recorded will be used to calculate the dose to be administered until the next weight measurement is obtained. Clinical Safety Laboratory Evaluations See Appendix A for details on specific routine serum chemistry, hematology, and urine analysis evaluations, as well as blood samples for hypersensitivity analysis as applicable. Safety laboratory tests will be performed at a central laboratory. Routine blood chemistry panels including liver function tests, a hematology panel including complete blood count with differential, and if feasible, routine urinalysis including urine dipstick, will be conducted to assess safety. Estimated glomerular filtration rate (eGFR) will be calculated by the Sponsor. Additional laboratory analytes may be requested by the Sponsor, including any performed at the Investigator’s discretion, if clinically indicated. Blood draws performed as part of study participant’s clinical care may be used for protocol -required safety laboratory evaluations. When feasible, leftover blood samples acquired Atty. Docket No.4427-12602 as part of the study participant’s clinical care will be retained for immunogenicity, PK, or biomarker assessments. Baseline (Day 1) clinical laboratory samples may be collected within 7 days prior to dosing on Day 1 and pre-dose with all other timepoints as indicated in Table 2. Immunogenicity Anti-drug antibodies to ENPP1-Fc will be assessed by a validated method. Samples will be stored to enable future testing including determinations of whether the antibodies are directed against the Fc or ENPP1 enzyme portions of ENPP1-Fc, when an appropriate assay is available. Blood will also be collected and stored to assess and further establish assays for specificity confirmation (i.e., titer) and neutralizing antibodies. Immunogenicity samples will be collected pre-dose in accordance with timepoints indicated in Table 2 Baseline (Day 1) immunogenicity samples may be collected within 30 days prior to dosing on Day 1. Additional samples for immunogenicity (outside of the time points specified in Table 2) may be collected if clinically indicated per Investigator discretion or upon Sponsor request. Peripheral blood mononuclear cells (PBMCs) isolated from a blood sample will also be collected any time during the Screening Period or prior to dosing on Day 1 and stored until a validated assay is available to assess the presence of cross-reactive immunologic material (CRIM), such as endogenous ENPP1. See Appendix A for immunogenicity evaluations. Immunogenicity and CRIM samples will be collected, processed, and shipped as outlined in the Laboratory Manual; assessments will be performed at a central laboratory. In the event of hypersensitivity reactions, including anaphylaxis, per Investigator’s discretion and / or upon Sponsor request, blood samples will be collected for the assessment of IgE and IgG antibodies and levels of acute phase reactants, serum tryptase, histamine, and complement activation (C3, C4). Additional samples may be obtained if clinically indicated per Investigator’s discretion and / or upon Sponsor request (e.g., in cases of suspected hypersensitivity reaction). See Appendix A for details on the hypersensitivity evaluations. Prior and Concomitant Medications or Therapies Prior medications include any drug (investigational, prescription, or over-the counter), biological product (such as vaccines, blood, or blood components), herbal remedies or preparations, and supplements received within 60 days prior to Study Day 1. Atty. Docket No.4427-12602 Use of concomitant medications will be assessed throughout the study and include any drug (prescription or over the counter), biological product (such as vaccines, blood, or blood components), herbal remedies or preparations, and supplements received after administration of the first dose of ENPP1-Fc, and throughout the study. All concomitant medications taken during the study will be recorded with indication, dose information, and dates of administration. Any changes to concomitant medication will also be documented. Non-drug therapies and medical / surgical procedures will be recorded. The medications received by participants for treatment of ENPP1 Deficiency will be specifically identified. Electrocardiogram Standard 12-lead ECGs will be collected pre-dose at the time points indicated in Table 2 and read centrally by a qualified vendor. Additional ECGs may be performed if clinically indicated by the Investigator. If an ECG is performed within 7 days of the first dose of ENPP1- Fc, it does not need to be repeated pre-dose on Day 1. Treatment Frequency An ENPP1 agent is administered at least once or twice bimonthly, at least once or twice monthly, three times monthly, at least once or twice weekly. In some embodiments, the ENPP1 agent is administered once a week. In some embodiments, the ENPP1 agent is administered twice a week to achieve a total dose of 2.4 mg of ENPP1 per kg bodyweight. In some embodiments, the ENPP1 agent is administered three times a week to achieve a total dose of 2.4 mg of ENPP1 per kg bodyweight. In some embodiments, the ENPP1 agent is administered four times a week to achieve a total dose of 2.4 mg of ENPP1 per kg bodyweight. In some embodiments, the ENPP1 agent is administered five times a week to achieve a total dose of 2.4 mg of ENPP1 per kg bodyweight. In some embodiments, the ENPP1 agent is administered six times a week to achieve a total dose of 2.4 mg of ENPP1 per kg bodyweight. In some embodiments, the ENPP1 agent is administered once every two weeks. In some embodiments, the ENPP1 agent is administered once every three weeks. In some embodiments, the ENPP1 agent is administered once a month. In some embodiments, the ENPP1 agent is administered once every five weeks. In some embodiments, the ENPP1 agent is administered once every six weeks. In some embodiments, the ENPP1 agent is administered once every seven weeks. In some embodiments, the ENPP1 agent is administered once every two months. In some embodiments, the ENPP1 agent is administered once every nine weeks. In some embodiments, the ENPP1 agent is administered once every ten weeks. In some embodiments, the ENPP1 agent Atty. Docket No.4427-12602 is administered once every eleven weeks. In some embodiments, the ENPP1 agent is administered once every three months. In some embodiments, the first dose of an ENPP1 agent may be administered on Day 1. On Days 8 to 29 and thereafter, the ENPP1 agent is administered to a subject at a selected dose of ENPP1 agent mg / kg doses twice weekly. In some embodiments, the study consists of a Screening Period of up to 60 days (including a washout period of up to 7 days for prohibited medications post-Randomization) and a Randomized Treatment Period (ENPP1-Fc or control) of 52 weeks, followed by an Open-label Extension Period of 52 weeks during which all study participants may receive ENPP1-Fc, and an End of Study (EOS) Safety visit 30 days after the last dose of ENPP1-Fc. The first dose may be administered on day 1 following the screening period of 60 days and the subsequent doses till the next 52 weeks may be administered once weekly or twice weekly. Preferably the dose is administered once weekly. The dose may be administered at approximately the same time on each dosing day. The site of injection is alternated, with no site within 2 inches of any prior site of injection within the prior 2 weeks. A selected dose of an ENPP1 agent of 2.4 mg / kg is administered SC over a time period determined by a medical practitioner skilled in the field of ENPP1 replacement therapy. The first dose of an ENPP1 agent may be administered on Day 1. After the first dose, a subject may be observed for 7 days to monitor safety and to collect PK samples. On Days 8 to 29, a subject receives a selected dose twice weekly or once weekly. Administration of an ENPP1 agent at a selected dose is continued as considered appropriate by the medical professional. A subject may receive 4 doses of an ENPP1 agent at 2.4 mg of ENPP1 polypeptide per kg of bodyweight of subject over the course of a 29-day period of time, if the dose is administered once weekly, resulting in an exposure of about 9.94 mg / kg total dose, for dose amounts of 2.4 mg / kg. A subject may receive 8 doses of an ENPP1 agent at 2.4 mg of ENPP1 polypeptide per kg of bodyweight of subject over the course of a 29-day period of time, if the dose is administered twice weekly, resulting in an exposure of about 19.2 mg / kg total dose, for dose amounts of 2.4 mg / kg. A subject may receive 52 doses of an ENPP1 agent at 2.4 mg of ENPP1 polypeptide per kg of bodyweight of subject over the course of a 52-week treatment period of time, if the dose is administered once weekly, resulting in an exposure of about 124.8 mg / kg total dose, for dose amounts of 2.4 mg / kg. Atty. Docket No.4427-12602 A subject may receive 104 doses of an ENPP1 agent at 2.4 mg of ENPP1 polypeptide per kg of bodyweight of subject over the course of a 52-week treatment period of time, if the dose is administered twice weekly, resulting in an exposure of about 249.6 mg / kg total dose, for dose amounts of 2.4 mg / kg. Like the endogenous ENPP1 enzyme, an ENPP1 agent cleaves ATP to generate AMP and PPi, thereby increasing plasma PPi levels and into AMP which CD73 coverts rapidly to adenosine. Replacement of the endogenous human enzyme is intended to correct the inherent deficiency and allow for improved health and mitigation of clinical complications associated with ENPP1 Deficiency. Thus, administration of ENPP1 agent (ENPP1-Fc) aims to treat, prevent or reduce the severity of one or more diseases including but not limited to Ectonucleotide Pyrophosphatase / Phosphodiesterase1 Deficiency, Hypopyrophosphatemia, Autosomal Recessive Hypophosphatemic Rickets (ARHR-2), Pseudoxanthoma elasticum (PXE) and Generalized Arterial Calcification of Infancy (GACI). Evaluation of Treatment Primary Outcome Measure: 1. To determine if ENPP1 agent such as ENPP1-Fc increases inorganic pyrophosphate (PPi) levels For each subject, their change from baseline in Plasma Inorganic Pyrophosphate (PPi) concentration will be assessed. [Time Frame: 52 weeks (Baseline through Week 52)] 2. To determine if ENPP1 agent such as ENPP1-Fc increases overall survival For each subject, their change in overall survival based on time from date of birth to event of all-cause mortality will be assessed. [Time Frame: 52 weeks (Baseline through Week 52)] Secondary Outcome Measure: 3. To determine if ENPP1 agent such as ENPP1-Fc prevents decline in cardiac ejection fraction For each subject, their change from baseline in left ventricular ejection fraction will be assessed via echocardiography. [Time Frame: 52 weeks (Baseline through Week 52)] 4. To determine if ENPP1 agent such as ENPP1-Fc prevents heart failure Atty. Docket No.4427-12602 For each subject, their incidence of heart failure will be assessed. [Time Frame: 52 weeks (Baseline through Week 52)] 5. To determine if ENPP1 agent such as ENPP1-Fc attenuates progression of arterial calcification For each subject, their change from baseline in vascular calcification in the coronary arteries and aorta will be examined via CT scan. [Time Frame: 52 weeks (Baseline through Week 52)] 6. To determine if ENPP1 agent such as ENPP1-Fc increases physical growth: body length and weight For each subject, their change from baseline in growth Z-score (body length and weight) and growth velocity will be assessed. [Time Frame: 52 weeks (Baseline through Week 52)] 7. To determine if ENPP1 agent such as ENPP1-Fc prevents respiratory dysfunction For each subject, the number of days on mechanical ventilation will be calculated and assessed. [Time Frame: 52 weeks (Baseline through Week 52)] 8. To characterize the PK and ENPP1 activity of ENPP1 agent such as ENPP1-Fc For each subject, their measurement of ENPP1-Fc plasma concentration and specific activity will be assessed. [Time Frame: 52 weeks (Baseline through Week 52)] Additional Parameters 1. Change from Baseline in growth Z-score (height / body length and weight) through Week 52. A Z-score represents the degree to which that particular measurement for that individual differs from the reference value in the general population. (height / body length and weight) through Week 52 [Time Frame: Baseline, Day 29, Week 8, Week 13, Week 26, Week 39, Week 52] 2. Area under the Plasma Concentration versus Time Curve (AUC) of ENPP1-Fc. For each subject, variation of concentration of ENPP1-Fc in the plasma will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. Atty. Docket No.4427-12602 (i) Pharmacokinetics ^ An ENPP1 agent plasma concentration-time profiles and determination of noncompartmental PK parameters (including Tmax, Cmax, AUClast, AUCtau, AUCinf, T1 / 2, Cmin, Cl / F and V / F) ^ Assess linearity between ascending ENPP1 agent SC doses and PK parameters. (ii) Pharmacodynamics ^ Change from baseline for plasma PPi levels, serum phosphate, plasma intact FGF23 levels, TmP / GFR (adjusted to creatinine clearance) ^ Assess linearity between ascending ENPP1 agent SC doses and PD parameters ^ Correlate the changes in PPi with changes in FGF23 ^ Correlate the changes in PPi with changes in TmP / GFR ^ Correlate the changes in FGF23 with changes in TmP / GFR ^ Exploration of presence and changes of blood and urine biomarkers ^ Plasma and urine creatinine (used to calculate the renal clearance of phosphate) ^ Serum 1,25(OH)2D, plasma ionized and total calcium, parathyroid hormone ^ Bone biomarkers: serum alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy terminal cross-linked telopeptide of type I collagen (CTx), and procollagen type 1 N-terminal propeptide (P1NP) (iii) Efficacy In order to assess treatment efficacy, determination of one or more of the following physical parameters may be made prior to and during treatment. ^ Baseline Skeletal ^ Bone density using DEXA ^ Na18F-PET / HR-pQCT (or HR-CT) ^ Baseline arterial and organ calcification ^ Na18F-PET / HR-pQCT (or HR-CT) ^ Echocardiogram ^ Baseline cardiovascular and peripheral vascular reactivity function ^ Stress Doppler echocardiography ^ ECG ^ Ankle-brachial Index ^ Pulse Wave Velocity ^ Peripheral arterial tonometry (PAT) ^ HRpQCT (or HR-CT) with and without contrast ^ Baseline neurological function ^ NIH Stroke Score Atty. Docket No.4427-12602 ^ Neurological exam ^ Baseline pulmonary function ^ Standard pulmonary function test ^ Baseline performance outcomes ^ - Hearing tests: Physical exam and otoscopy, immittance audiometry (tympanometry), Pure Tone Audiometry (PTA), High Frequency Audiometry (HFA) ^ Baseline patient, clinician, and caregiver outcomes - Patient and Physician Global Impression of Change (CGI-C and CGI-S) - Gross Motor Function Classification System - Expanded and Revised - PROMIS Pain Interference and pain intensity - PROMIS Fatigue, mobility, cognitive impact, upper extremity - Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Stiffness Score ^ Baseline renal calcification as measured by renal ultrasound ^ Baseline bone histomorphometry using bone biopsy (optional) ^ Baseline optical coherence tomography of aorta, coronary arteries, carotid arteries, and renal arteries and vascular beds. OBJECTIVES, ENDPOINTS AND ESTIMANDS The primary objectives of the study, corresponding endpoints and estimands to be evaluated are listed in Table 6. Table 6: Study Objectives, Endpoints, and Estimands for Primary Analyses Atty. Docket No.4427-12602 The estimands in the study are defined through the following 5 attributes: ^ Population*: Intent-to-treat (ITT) analysis set includes all enrolled participants and a matched historical control dataset ^ Treatment*: The treatment regimen of interest in this study is ENPP1-Fc. ^ Endpoint: See description of endpoints in Table 6. ^ Strategy for addressing intercurrent events: See description of intercurrent events in Table 6. ^ Population-level summary: o Difference in means of PPi between ENPP1-Fc at baseline and at post study drug dose time points using a one-way analysis of variance (ANOVA). Atty. Docket No.4427-12602 − The intercurrent events that will be considered are: treatment discontinuation, lost to follow-up, and withdrawal from the study. − The intercurrent events will be handled with a treatment policy strategy whereby any measured value will be used as is. o Difference in length of survival between ENPP1-Fc treated subjects and a matched historical control dataset − The intercurrent events that will be considered are: treatment discontinuation, lost to follow-up, and withdrawal from the study. − The intercurrent events will be handled with a treatment policy strategy whereby any measured value will be used as is. The co-primary endpoints will consist of 2 different populations for analysis, where all enrolled study participants in Study will constitute the active arm and an external historical control dataset will be employed as an active comparator in the survival analysis. Safety and Immunogenicity Safety assessments may be summarized at Baseline and at each observed time point. Safety variables include: ^ Incidence, frequency, and severity of adverse events (AEs), treatment-related AEs, and serious adverse events (SAEs) ^ Vital signs and weight ^ Physical examinations ^ Estimated glomerular filtration rate (eGFR) ^ Laboratory tests including chemistry, hematology, and urinalysis, including additional biochemical parameters of interest ^ Anti-ENPP1-FC antibody testing and dose-limiting toxicities (DLTs) ^ Incidence of any anti-drug antibodies (ADA) ^ Incidence of TEAEs associated with hypersensitivity reactions ^ Concomitant medications ^ Electrocardiogram (ECG) Atty. Docket No.4427-12602 Adverse Event An adverse event (AE) is any untoward medical occurrence (e.g., sign, symptom, illness, disease, injury, including clinically significant abnormal laboratory findings) in a study participant administered any amount of ENPP1-Fc or other protocol-imposed intervention regardless of attribution after signing of the informed consent. Treatment-emergent AEs are defined as any AE that newly appears (if clinically significant) or a pre-existing condition that changes in nature, severity, or frequency, following initiation of ENPP1-Fc. A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug caused the AE. Serious Adverse Event An SAE is an event that results in any of the following: ^ Death ^ Life-threatening Note: Life-threatening refers to an event that places the study participant at immediate risk of death. This definition does not include a reaction that, had it occurred in a more severe form, might have caused death. ^ A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions ^ Inpatient hospitalization or prolongation of existing hospitalization. Examples of visits to a hospital facility that do not meet the seriousness criteria for hospitalization include: o Outpatient surgery o ER visits that do not result in hospital admission o Pre-planned or elective procedures o Protocol procedures • An important medical event that, based on appropriate medical judgment, may jeopardize the study participant and may require medical or surgical intervention to prevent one of the outcomes listed above (e.g., anaphylaxis) Injection Site Reactions Signs and symptoms of injection site reactions (ISRs) include swelling, erythema, induration, pruritus, pain, and other relevant signs and symptoms adjacent to the site of injection. If an ISR is identified by the Investigator as a component of a hypersensitivity reaction, the signs Atty. Docket No.4427-12602 and symptoms of the ISR will be recorded in the database as components of the hypersensitivity reaction. Adverse Events of Special Interest (AESI) The following AESIs will be evaluated: ^ systemic hypersensitivity reactions, including anaphylaxis ^ seizures A systemic hypersensitivity reaction comprised of multiple signs and symptoms will be reported as a single event; the signs and symptoms comprising the systemic hypersensitivity reactions will be recorded in the clinical database and the reaction will be graded according to the most severe sign or symptom. The list of events of special interest will be updated based on emerging data and will be reviewed for addition to the reference safety information. Any change to the reference safety information will be communicated to the sites by the Sponsor or their designee. Severity Assessment Severity (e.g., NCI-CTCAE Grade 1, 2, 3, etc.) is not equivalent to seriousness, which is based on patient / event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. The Investigators will use their judgment to determine the severity of each particular AE / SAE by following the grading criteria specified in CTCAE version 5.0 (NCI 2017) as applicable for that specific AE / SAE and as applicable for the patient population in this clinical study (e.g., pediatrics). If the specific AE / SAE is not found in the CTCAE version 5.0 document, or if the CTCAE reference ranges are not appropriate for the pediatric population based on clinical significance and level of intervention needed, the Investigator will follow the general guidelines (principles) for AE / SAE severity grading, as stated in the introductory section of the CTCAE version 5.0 document and excerpted from that document below in Table 7. Table 7: Adverse Event Severity Grading Scale Atty. Docket No.4427-12602 a. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. b. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. ADL=activities of daily living; AE=adverse event; SAE=serious adverse event. Source: CTCAE v5 (NCI 2017) Causality Assessment The Investigator will determine the causality / relationship of each AE as described in Table 8 and will record it. Table 8: Adverse Event Causality Attribution Guidance AE=adverse event. Persistent or Recurrent Adverse Events A persistent AE is one that continues, without resolution, between study participant evaluation time points. Such an event should be recorded only once, and the highest grade of severity should be reported. The end date for the first entry will be the start date for the new entry. Atty. Docket No.4427-12602 Events that resolve but recur should be recorded as separate AEs, each with their own start and stop dates and each graded according to the highest grade of severity noted. Pre-existing Conditions A pre-existing condition is one that is present at the time the ICF is signed; such conditions should be recorded as medical history. A pre-existing condition should be recorded as an AE / SAE during the study only if the frequency, intensity, or character of the condition worsens during the study period. It is important to convey the concept that a pre-existing condition has changed by including applicable language in the verbatim description of the event (e.g., more frequent headaches). Physical Examination Findings Prior to Study Day 1, any clinically significant abnormality should be recorded as a pre- existing condition (i.e., part of medical history). After Study Day 1, any new clinically significant findings and / or abnormalities discovered on physical examination that meet the definition of an AE / SAE must be recorded as such. Abnormal Laboratory Results A clinical laboratory abnormality will be reported as an AE if deemed to be clinically significant by the Investigator. Examples that suggest clinical significance include: ^ Accompanied by clinical symptoms ^ Leading to a change in ENPP1-Fc (e.g., dose modification, interruption, permanent discontinuation) ^ Requiring a change in concomitant therapy (e.g., addition of, interruption of, discontinuation of, any other change in a concomitant medication, therapy, or treatment) ^ The abnormality suggests a disease and / or organ toxicity ^ The abnormality is of a degree that requires active management (e.g., discontinuation of ENPP1-Fc, more frequent follow-up assessments, further diagnostic investigation) This applies to any protocol or non-protocol specified safety and laboratory result from tests performed after Study Day 1 that falls outside the laboratory reference range and meets the clinical significance criteria. This does not apply to any abnormal laboratory result that falls outside the laboratory reference range but that does not meet the clinical significance criteria Atty. Docket No.4427-12602 (these will be analyzed and reported as laboratory abnormalities), those that are considered AEs of the type explicitly exempted by the protocol, or those which are a result of an AE that has already been reported. Any laboratory result abnormality fulfilling the criteria for an SAE should also be reported. STATISTICAL METHODS General Principles The efficacy analyses for the PK parameters will be based on the PK analysis set (PKAS), all other efficacy analyses will be based on the ITT analysis data set; the safety analyses will be based on Safety Analyses Set. Descriptive statistics will be used to summarize the data. For continuous variables, the mean, standard deviation, standard error, median, interquartile range (Q1, Q3), minimum and maximum will be provided. For discrete data, the frequency and percentage distributions will be provided. Statistical tests will be two-sided at the alpha = 0.05 significance level, unless specified. No adjustment on multiplicity will be made for statistical comparisons unless stated otherwise. A sub-analysis of study participants from the EAP will be conducted. Study Conduct Analysis Enrollment, important protocol deviations, and study participant disposition (e.g., discontinuations from study treatment and from study and reported reasons) will be listed and summarized for all study participants. Population Characteristics Study participant demographics, disease, and baseline characteristics will be summarized using appropriate descriptive statistics for all participants. Study Populations The following populations will be analyzed: • ITT analysis data set includes all study participants enrolled into the study, including those who do not receive a dose of the assigned study medication, and all observed data from each study participant regardless of compliance and adherence with the assigned treatment regimen or with follow-up schedule. • Safety analysis set includes all enrolled study participants receiving at least a partial dose of ENPP1-Fc. • Pharmacokinetic analysis set (PKAS): is a subset of the SAS including study participants with evaluable ENPP1-Fc PK data. Atty. Docket No.4427-12602 Primary Efficacy Analyses The co-primary efficacy endpoint 1 is the change from Baseline over time in plasma PPi concentrations through Week 52. Descriptive statistics will be provided for observed value in plasma PPi and changes from baseline at each visit. The One-Way Repeated Measures ANOVA model will be applied to obtain 95% confidence interval (CI) and p-values. The co-primary efficacy endpoint 2 is the overall survival based on time from date of birth to event of all-cause mortality. This endpoint will be calculated as the time from birth to the occurrence of death from any cause. All study participants will have some information regarding mortality and last visit of follow-up. Study participants without any observed death at the time of analysis will be censored at their last visit or contact. The Cox proportional hazard regression model will be employed to adjust for a set of covariates, or to jointly assess the influence of a set of factors simultaneously. The analysis of survival time to event endpoint will be based on a statistical comparison between this interventional arm (ENPP1-Fc) and a historical control arm. The historical control is created with the extracted dataset formed by all patients from the National Institute of Health (NIH) database, which is filtered by the study inclusion / exclusion criterion listed above. The study patients in the historical control arm will be selected with the following two-stage propensity score / Mahalanobis distance matching approach. At the first stage, by baseline categorical covariate(s) all the patients in this intervention arm and extracted dataset will be assigned into different clusters, the combinations formed by the levels or cross of covariates’ levels of key categorical factor(s). If there are both categorical and numerical covariates available from baseline measurements, logistic model-based propensity score will be compared with all valid information from baseline measurements for all patients within each cluster. If there are only continuous numeric covariates available from baseline measurements, the Mahalanobis distances between each patient from the intervention arm and all patients from the extracted dataset within the same cluster are calculated to exclude all the possible bias caused by mis-specified propensity score computation model. At the second stage, via propensity score / Mahalanobis distance with optimal algorithm, 1 (patient intervention arm) to k (up to 5 patients from extracted dataset) match ratio will be applied in control arm patient selection within each cluster. The possible missing covariates’ value in extracted dataset will be handled with the statistical analysis described below. Through this two-stage procedure, appropriate balance of baseline covariates between intervention arm and historical control arm will be achieved. This approximate balance of baseline covariates will minimize their confounding effects on efficacy and safety endpoints, through which this real-world evidence study design mimics the parallel test and control clinical trial. Atty. Docket No.4427-12602 Considering the compromising among balance, efficiency and variation among study patients between intervention arm and historical control arm, the matching ratio 1: k (k up to 5) will be applied for the matching algorithm within each cluster for this study design. To reduce the dominance in sample size of historical control arm, a weight indicator is created for this analytical dataset, which will apply in the statistical comparison. Weighted Kaplan-Meier survival curves will be estimated for treated and untreated study participants in the propensity score / Mahalanobis distance matched samples. Weighted log-rank test will be used to compare the equality of the survival curves in the matched sample. Descriptive statistics will also include the number of patients at risk, number of patients with events, the incidence (proportion of patients with events), the time at risk of event and the incidence rate from this non-parametric model-based survival analysis. A full description of the statistical evaluations, general considerations, and procedures for analysis of the data will be provided in the SAP. Secondary Efficacy Analyses The secondary endpoints will be summarized using descriptive statistics and are as follows: • Change from Baseline in left ventricular ejection fraction via echocardiography through Week 52 • Incidence of heart failure • Change from Baseline in vascular calcification in the coronary artery and aorta via CT scan through Week 52 • Change from Baseline in growth Z-score (body length and weight) through Week 52 • Growth velocity • Number of days of mechanical ventilation • Measurement of ENPP1-Fc plasma concentration and specific activity No formal analyses are pre-planned for the secondary endpoints. Descriptive statistics will be provided for secondary, tertiary and safety endpoints and will be detailed in the SAP. Tertiary Efficacy Analyses For the tertiary endpoints (healthcare resource utilization, biomarkers, Bayley-3, anti- hypertensive medication use, and oxygen saturation <85%), the details of analyses will be provided in the SAP. Missing Data Missing Baseline Covariate Data Atty. Docket No.4427-12602 To handle missing covariate values in the extracted dataset from the NIH (the database) for patient selection of historical control arm through two-stage matching with propensity score / Mahalanobis distance, the following expectation-maxima (E-M) likelihood optimal imputation method will be utilized based on the rational assumption of missing at random (MAR). A covariate will be ignored in the patient selection procedure if the missing value rate of the covariate is greater than 35%. In this optimal algorithm, the missing value of categorical covariate will be imputed with prediction of mixed effect logistic regression, and the missing value of the continuous numerical variable is imputed with the prediction of linear mixed effect model. After about 10 E-M iterations, all the missing values will be filled with an optimal prediction value, which will be the final dataset for patient matching procedure. Missing Outcome Data It is anticipated there would be minimal loss to follow-up for the assessment of the primary outcome. All efforts will made to ensure near complete follow-up in particular with the assessment of the primary outcomes. Since all enrolled study participants are included in the primary efficacy analyses, study participants missing outcome data will be censored at the last follow-up assessment time. Repeatedly measured data, defined as outcome data, will be addressed using likelihood- based statistical models that allow inclusion of all enrolled participants having at least one post- enrollment measure in the analysis of the primary and secondary outcomes. For outcomes measured on one occasion after Baseline and where more than 5% of the outcome data is missing, multiple imputation (MI) assuming MAR will be used to impute missing observations. Sensitivity analyses to assess the robustness of the primary analysis result to missing data, will be conducted on the primary endpoint. These analyses may include but are not limited to: • Last Observation Carried Forward (LOCF): The last non-missing post-baseline observation will be carried forward in the corresponding endpoint for evaluation. If no post-baseline observation is available, the Baseline observation will be used for evaluation. If no Baseline is available, the LOCF approach will not be performed. • Multiple Imputation (MI): MI using a Markov Chain Monte Carlo (MCMC) approach by 100 times. Sensitivity to Missing Data Mechanism The mixed models for repeated measures (MMRM) statistical model for analysis of the co-primary endpoint 1 outcome is MAR. While MAR is likely to be plausible for the majority of missing values, sensitivity to the MAR assumption will be assessed by analyzing data with models that assume plausible data, Missing Not At Random (MNAR). Atty. Docket No.4427-12602 A full description of the statistical evaluations, general considerations, and procedures for analysis of the data will be provided in the SAP. Safety Analyses Safety evaluations will include AE and SAE reporting (including AESI), ECGs, vital signs (temperature, respiratory rate, oxygen saturation, blood pressure, and heart rate), physical examination, clinical laboratory parameters (hematology, serum chemistry, and urinalysis), concomitant medication reporting, and immunogenicity. An analysis of the incidence of heart failure will be conducted. Safety data will be listed and summarized by dose and visit with descriptive statistics. The safety endpoints will be evaluated by examining incidence and type of TEAEs, including clinically significant changes from Baseline through the EOT Visit in clinical laboratory parameters, physical examination results, vital signs measurements, and ECG parameters that result in TEAEs. Treatment-emergent AEs will be summarized using frequency counts and percentages. Treatment-emergent AEs will also be summarized by NCI-CTCAE version 5 grade and relationship to ENPP1-Fc. In addition, all SAEs, deaths, and AEs leading to ENPP1-Fc discontinuation will be summarized and listed separately. Extent of Exposure The extent of study treatment will be assessed, and summary statistics will be presented for the SAS. Timing of Analysis Available safety data will be evaluated throughout the study. A primary analysis will be conducted once data are available from the last study participant completing the last protocol-specified assessment through Week 52 of the Treatment Period. A final analysis will be conducted when the last study participant leaves the study as noted above in Table 3. Determination of Sample Size Recruitment is limited by the extremely low prevalence and the ultra-rare nature of the disease. This Phase 3 study is powered to test the effect of ENPP1-Fc on increasing PPi in children with ENPP1 Deficiency. A 2-sided, one sample cure model test calculated for the survival endpoint from a sample size of 12 study participants achieves at least 84% power at 0.05 significance level to detect a cure rate of 0.9 in the treated group when the cure rate in the historical control group is 0.4 Atty. Docket No.4427-12602 and / or detect a median survival time of 1.2 years in the treated group when the median survival in the control group is 1 year. Study participants are accrued for a period of 1 year. Follow-up continues for a period of 1 year after the last participant is added, and it is assumed that the survival time distribution is approximated reasonably well by the exponential distribution. For the analysis of PPi, a sample size of 8 achieves 84.6% power to detect a 60% increase from Baseline PPi within an individual averaged across time, using a test with significance level of 0.05 from a mixed model fit without the treatment-by-center interaction. Since this is a co- primary endpoint, sample size has been calculated separately; however, a larger sample size of 12 has been selected as the overall sample size for this study. Table 9 – Glossary of Terms Atty. Docket No.4427-12602 Atty. Docket No.4427-12602 Atty. Docket No.4427-12602 APPENDIX A. CLINICAL LABORATORY ANALYTES Atty. Docket No.4427-12602 Sample collection, and processing are done following well established clinical trial sample collection protocols . The Investigator will determine the maximum volume of blood that may be collected in accordance with the protocol and the allowable limits for the study participant’s weight and / or age per institutional requirements and / or guidelines. If necessary, the Investigator may conduct blood sampling over multiple days for visits with an allowable ± window. Urine will be collected if feasible. a. Tests for hypersensitivity reaction, including anaphylaxis, will be performed per Investigator’s discretion and / or upon Sponsor request. 1,25-(OH)2D3=active vitamin D3; CRIM= cross-reactive immunologic material; eGFR=estimated glomerular filtration rate; ENPP=ectonucleotide pyrophosphatase / phosphodiesterase 1; EOT=End of Treatment; FGF23=fibroblast growth factor 23; Ig=immunoglobulin; P1NP=Procollagen type 1 N-terminal propeptide; PPi=inorganic pyrophosphate Rationale for Dose Selection and Dosing Schedule To determine optimal dosing of ENPP1-Fc in this study, the investigators evaluated the following data and information: ^ Nonclinical study data used to simulate human dosing o Clinical study data including safety, PD, and PK data from three clinical studies in adults and infants with ENPP1 Deficiency, and adults with ABCC6 Deficiency (Studies INZ701-101, INZ701-104, and INZ701-201, respectively) ^ Population PK modelling Atty. Docket No.4427-12602 Nonclinical Studies and Simulation Data Nonhuman primate PK data and mouse PD data were used to simulate dosing of 0.2 mg / kg, 0.6 mg / kg, and 2 mg / kg ENPP1-Fc given twice weekly in adult patients. These simulations show that these doses should restore PPi levels to the normal range in ENPP1- deficient patients. A noncompartmental analysis was used to simulate expected metrics of exposure in man. This analysis showed that the maximum exposure level, based on the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUClast) were approximately 4.8- fold and 12-fold, respectively, below the No Observed Adverse Effect Level (NOAEL) defined in nonclinical studies. Clinical Studies ENPP1-Fc has exhibited a favorable safety profile at all dose levels tested (0.2, 0.6 and 1.8 mg / kg of bodyweight of subject administered twice weekly) in adults with ENPP1 Deficiency and ABCC6 Deficiency. Preliminary clinical PK / PD data from 9 adult participants with ENPP1 Deficiency from Study INZ701-101 showed a rapid (within 6 hours) and sustained increase in mean plasma PPi levels after a single dose of ENPP1-Fc at Day 1 and twice weekly ENPP1-Fc administration commencing at Day 8. These increased PPi levels were comparable to those observed in a study of healthy adult study participants. Uniform response and consistent predictable PPi levels in the normal range will be important to ensure a rapid and durable response to therapy. The 3 doses tested (0.2, 0.6, and 1.8 mg / kg of bodyweight of subject given subcutaneously [SC] twice weekly) were effective in restoring mean PPi levels in adult participants in the INZ701-101 study. However, there was a heterogeneous PPi response among the ENPP1-Fc doses, and investigators has concluded that in adults, the 1.8 mg / kg dose is optimal to ensure a uniform PPi response to reach and sustain normal PPi levels with the lowest variability. In addition, analysis of biomarker data suggests a dose response favoring the 1.8 mg / kg dose level. Pharmacokinetic analysis in adults with ENPP1 Deficiency showed that the mean half- life of ENPP1-Fc was approximately 126 hours, suggesting the potential for once-weekly dosing. PK analysis in adults with ABCC6 Deficiency was consistent. Data from 2 infants with ENPP1 Deficiency in Study INZ701-104 demonstrate that ENPP1-Fc was generally well-tolerated at doses up to 0.6 mg / kg twice weekly. A total of 22 AEs have been reported in the 2 enrolled participants; all have been Grade 1 and there have been no SAEs. No anti-drug antibodies (ADAs) were detected by Day 32 in either participant. Low titers (320 and 2560) of neutralizing ADAs were observed at Week 13, but were not associated with AEs. Preliminary PK data from the first 2 participants of Study INZ701-104 show initial drug accumulation. Preliminary PD data from the first 2 participants of Study INZ701-104 Atty. Docket No.4427-12602 demonstrated that twice per week administration of ENPP1-Fc at a dose level of 0.2 mg / kg, led to a rapid increase in plasma PPi levels within a week and increased further after Day 22 in both participants. Population PK Modeling Investigators conducted a PK modelling study to evaluate the proposed dose interval using PK data from adults and infants, and one Expanded Access Program (EAP) pediatric patient with ENPP1 Deficiency (Study INZ701-101; ENERGY: INZ701-104; INZ701-EAP-01, respectively) and ABCC6 Deficiency (Study INZ701-201). This study showed that at all dose levels, once-weekly dosing results in relatively consistent serum concentrations of ENPP1-Fc and that ENPP1-Fc concentrations in excess of 3000 ng / mL could be obtained with once-weekly 1.8 mg / kg dosing. At this serum concentration, substantial elevations of PPi into the normal range have been observed in the Phase 1 / 2 studies in adults. These results support once-weekly dosing in future clinical studies. Investigators have completed a modeling study, to elaborate on the population PK modeling, in which the area under the curve (AUC) over the weekly dosing interval was simulated in pediatric and adult patients. In the model, age-dependent exponents were added to the body weight covariate effect on clearance to account for maturation effects on ENPP1-Fc clearance. The study concluded that it is possible that once-weekly dosing could result in ENPP1-Fc exposure within the desired therapeutic range. Furthermore, candidate pediatric doses could be chosen to match the median adult AUC from 1.8 to 2.4 mg / kg over a once-weekly dosing interval after the seventh dose at steady state. The results of the analysis are shown in Table 10. Table 10: Infant and Pediatric Doses to Match Adult Steady State ENPP1-Fc AUC at 1.8 and 2.4 mg / kg Atty. Docket No.4427-12602 AUC=area under the curve. Dose Rationale Conclusions The dose for the infant study participants in this clinical study is 2.4 mg / kg once-weekly dosing. This dose was selected for this study based on the following rationale: Investigators consider the optimal adult dose observed in Study INZ701-101 to be 1.8 mg / kg twice weekly, primarily because each of the study participants reached normal PPi levels that were sustained within normal reference range with the lowest variability. In addition, biomarker data demonstrated a dose response, favoring the 1.8 mg / kg dose. ^ Once-weekly dosing is supported by the relatively long half-life of ENPP1-Fc. Weekly dosing will reduce injection frequency, minimize injection site reaction risk and increase compliance. Population PK modeling indicates that a dose of 2.4 mg / kg weekly in the infant population will provide a good exposure level of ENPP1-Fc along with a good safety coverage relative to the exposure levels of ENPP1-Fc in adults when dosed twice weekly at 1.8 mg / kg (Table 10). ^ The safety profile at the 1.8 mg / kg twice weekly dose appears to be comparable to lower doses in Study INZ701-101. ^ In toxicology studies the NOAEL was 74,400 week*ng / mL for AUClast. Based on this dosing strategy, the anticipated maximum exposure levels in this study will be approximately 13.2-fold below the NOAEL in participants aged 0 to <12 months. Benefits It is expected that ENPP1 agent such as ENPP1-Fc will restore ENPP1 activity, which in turn may allow the circulating levels of PPi, an important regulator of calcification and cell proliferation, to reach therapeutically effective levels. The results from the Sponsor’s nonclinical pharmacology studies clearly demonstrated the therapeutic effects of ENPP1 agent such as ENPP1-Fc in prevention of both pathological calcification and intimal proliferation in murine models of ENPP1 Deficiency, as well as a decrease in mortality in ENPP1-deficient mice. Positive preliminary clinical data from an interim analysis of Study INZ701-101 in adults with ENPP1 Deficiency included the following: Atty. Docket No.4427-12602 ^ Rapid, significant, and sustained increase in PPi levels observed in all patients and significant elevation in PPi maintained for up to 18 months ^ Meaningful reduction of FGF-23 ^ Serum Pi levels increased over time ^ Statistically significant correlation between increase in PPi and decrease in FGF- 23 observed at one week post first dose ^ Upward trends observed in bone specific alkaline phosphatase (BSAP) levels from baseline ^ Concordant improvement in Global Impression of Change (GIC) scores reported by patients (P-GIC) and clinicians (C-GIC) ^ High responder rates in the Patient-Reported Outcome Measurement Information Scales (PROMIS) of pain intensity, fatigue and pain interference ^ Trend of improvement in 6-minute walk test Without being bound by theory, it is believed that ENPP1 agent such as ENPP1-Fc upon administration to infants with ENPP1 deficiency under the age of one at a dosage of 2.4 mg / kg once a week would yield similar results and improvements. EXEMPLIFICATION The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain embodiments and embodiments of the present invention and are not intended to limit the invention. Example 1. Generation of ENPP1 fusion proteins One example of an ENPP1 fusion protein is ENPP1-Fc. However, the exemplification of ENPP1-Fc can be applied to other ENPP1 fusion proteins as set forth herein. ENPP1-Fc is a recombinant fusion protein that contains the extracellular domains of human ENPP1 (soluble ENPP1) coupled with an Fc fragment of IgG1 (rhENPP1-Fc). The recombinant extracellular domains of ENPP1-Fc contain its catalytic activity and are identical to the native ENPP1 enzyme. ENPP1-Fc is a recombinant human protein produced in CHO cells via a fed batch cell culture process that is free of animal-derived components. The molecular weight of the ENPP1-Fc dimer is approximately 290 kDa; ENPP1-Fc is highly glycosylated and has a pI of approximately 6.0. Like endogenous ENPP1, the primary substrate for ENPP1-Fc is ATP, which is cleaved to AMP and PPi. Atty. Docket No.4427-12602 In a specific embodiment, soluble ENPP1 protein was fused to a human Fc domain with a linker via a linker (comprising a leucine, isoleucine, and asparagine). Three ENPP1-Fc constructs are shown in Table 1 as SEQ ID NOs: 3, 4, and 5 as purified from CHO cells. Purification of ENPP1-Fc could be achieved by a series of column chromatography steps, including, for example, three or more of the following, in any order: protein A chromatography, Q sepharose chromatography, phenylsepharose chromatography, size exclusion chromatography, and cation exchange chromatography. The purification could be completed with viral filtration and buffer exchange. Following purification of the protein, the catalytic activity of the ENPP1- Fc protein could be evaluated using pNP-TMP as a chromogenic substrate. Example 2: Treatment ENPP1-FC is administered to an infant of the age of 7 days at a dosage of 2.4 mg / kg. Administration is subcutaneous (SC) at least once or twice bimonthly, at least once or twice monthly, three times monthly, at least once or twice weekly. The first dose of ENPP1-Fc may be administered to an infant on Day 1. On Days 8 and thereafter, ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1 agent of 2.4 mg / kg doses once weekly. The dose may be administered at approximately the same time on each dosing day. The site of injection is alternated, with no site within 2 inches of any prior site of injection within the prior 2 weeks. A selected dose of ENPP1-Fc is 2.4 mg / kg SC to an infant of the age of 7 days. The first dose of ENPP1-FC may be administered on Day 1. After the first dose, the infant may be observed for 7 days to monitor safety and to collect PK samples. On Days 8 and thereafter, an infant of the age of 7 days receives a selected dose once weekly. In some embodiments, on Days 8 and thereafter, an infant of the age of 7 days receives a selected dose once weekly. Administration of ENPP1-Fc at a selected dose is continued as considered appropriate by the medical professional. An infant of the age of 7 days may receive 4 doses of ENPP1-Fc at 2.4 mg / kg per bodyweight over the course of a 29 day period of time, for example, resulting in a total exposure of 9.6 mg per 29 days at once a week dosage or an infant of the age of 7 days may receive 8 doses of ENPP1-FC over the course of a 29 day period of time, for example, resulting in a total exposure of 19.2 mg per 29 days at twice a week dosage for dose amounts of mg / kg respectively. Or an infant of the age of 7 days may receive more or less than 8 doses, as considered appropriate by a medical profession. Like the endogenous ENPP1 enzyme, ENPP1-Fc cleaves ATP to generate AMP and PPi, thereby increasing plasma PPi levels and into AMP which CD73 coverts rapidly to adenosine. Replacement of the endogenous human enzyme is intended to correct the inherent deficiency and Atty. Docket No.4427-12602 allow for improved health and mitigation of clinical complications associated with ENPP1 Baseline patient, clinician, and caregiver outcomes. Example 3: Treatment of a Patient Having an ENPP1 Deficiency ENPP1-Fc is administered to an infant of the age of 7 days identified as having an ENPP1 deficiency by subcutaneous injection on Day 1 and once or twice weekly starting on Day 8 at 2.4 mg / kg. ENPP1-Fc is administered an infant of the age of 7 days at a selected dose of ENPP1-FC is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. The infant’s response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of ENPP1 deficiency, and / or using guidance provided herein. In some instances, the study period for evaluating the efficacy of treating ENPP1 deficiency using ENPP1-Fc at different dosages is an extended study period of 338 days (Phase II) or 364 days or 52 weeks (Phase III). The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 4: Treatment of a Patient Diagnosed with GACI ENPP1 deficiency may mask as GACI. GACI is a rare disease occurring in infants and involving extensive arterial calcification (Albright, et al., 2015, Nature Comm.10006). ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- Fc is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. GACI Patient response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of GACI, and / or using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 5: Treatment of Patient Diagnosed with ARHR2 ENPP1 deficiency may mask as ARHR2. ARHR2 is a rare skeletal disorder characterized by low levels of plasma PPi and serum phosphate which can result in rickets, repeated fractures of the long bones, rachitic skeletal deformities and impaired growth and development (Ferreira et al 2014, Moran 1975, Rutsch et al 2008). ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the Atty. Docket No.4427-12602 medical professional. ARHR2 Patient response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of ARHR2, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 6: Treatment of a Patient Having an ABCC6 Deficiency ENPP1-Fc is administered to an infant of the age of 7 days identified as having an ABCC6 deficiency by subcutaneous injection on Day 1 and once weekly starting on Day 8 using a select dose of 2.4 mg / kg. ENPP1-Fc is administered at a selected dose of ENPP1-Fc of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. The infant’s response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of ABCC6 deficiency, and / or using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 7: Treatment of Patients (female and male) Diagnosed with PXE having an ABCC6 deficiency A Phase III, Open-Label, single Dose Study is performed in infants of ages between 0 days to less than 12 months in order to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ENPP1-Fc. This is followed by an Open-Label Long-Term Extension Period in infants of ages from 0 days to under 12 months with ABCC6 Deficiency Manifesting as Pseudoxanthoma Elasticum (PXE). Atty. Docket No.4427-12602 Outcome Measures Measures of Primary and Secondary Outcomes are as follows. Primary Outcome Measure: 1. Number of Treatment Emergent Adverse Events (TEAEs) [Time Frame: 32 days (Dose Evaluation Period)] Treatment-emergent AEs are defined as any AE occurring from the first dose of ENPP1-Fc through 30 days after the last dose of ENPP1-Fc. 2. Number of Treatment Emergent Adverse Events (TEAEs) [Time Frame: 52 weeks (Day 1 through Safety Follow-up Visit)] Treatment-emergent AEs are defined as any AE occurring from the first dose of ENPP1- Fc through 30 days after the last dose of ENPP1-Fc. Secondary Outcome Measures: 1. Incidence of Anti-Drug Antibodies (ADAs) [Time Frame: 32 days (Dose Evaluation Period)] The presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes. 2. Incidence of Anti-Drug Antibodies (ADAs) [Time Frame: 52 weeks (Day 1 through Safety Follow-up Visit)] The presence of ADAs will be assessed and, if present, further evaluation will determine specificity and subtypes. 3. Area under the Plasma Concentration versus Time Curve (AUC) of ENPP1-Fc [Time Frame: 32 days (Dose Evaluation Period)] For each subject, variation of concentration of ENPP1-Fc in the plasma will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. 4. Maximum Plasma Concentration (Cmax) of ENPP1-Fc [Time Frame: 32 days (Dose Evaluation Period)] For each subject, the maximum concentration of ENPP1-Fc in the plasma will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. Atty. Docket No.4427-12602 5. Systemic Clearance of ENPP1-Fc [Time Frame: 32 days (Dose Evaluation Period)] For each subject, clearance of ENPP1-Fc from the body will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. 6. Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels [Time Frame: 32 days (Dose Evaluation Period)] For each subject, plasma PPi will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. 7. Change from Baseline in Plasma Inorganic Pyrophosphate (PPi) Levels [Time Frame: 52 weeks (Baseline through Safety Follow-up Visit)]. For each subject, plasma PPi will be measured via a series of blood samples obtained throughout the study, comparing the subject's baseline value over time. Eligibility Criteria Ages Eligible for Study: Under 12 months of age Sexes Eligible for Study: All Gender Based: No Accepts Healthy Volunteers: No Criteria for Inclusion and Exclusion Inclusion and Exclusion Criteria are as follows. Inclusion Criteria: 1. Must provide written or electronic consent after the nature of the study has been explained, and prior to any research-related procedures, per ICH GCP 2. Clinical diagnosis of PXE supported by prior genetic identification of biallelic ABCC6 mutations 3. Male or female, under 12 months of age at Screening 4. Plasma PPi < 1300nM at Screening 5. Subjects who are being treated with statins or proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors must be on stable doses prior to enrollment through end of study unless the investigator deems, in consultation with the Sponsor, that the change will not confound interpretation of the study data Atty. Docket No.4427-12602 6. Parent or guardian must agree to provide access to relevant medical records Exclusion Criteria: 1. In the opinion of the Investigator, presence of any clinically significant disease (outside of those considered associated with the diagnosis of ABCC6 Deficiency) that precludes study participation or may confound interpretation of study results, including known uncontrolled thyroid disease or unrelated connective tissue, bone, mineral, ophthalmologic, or muscle disease 2. Advanced eye disease requiring anti-VEGF treatment at Screening 3. Clinically significant abnormal laboratory result at Screening. 4. Screening laboratory results demonstrating elevations of aspartate aminotransferase, alanine aminotransferase, bilirubin (unless due to Gilbert disorder), eGFR >60, 25-hydroxyvitamin D (25[OH]D) levels <20 ng / mL, parathyroid hormone (PTH) >40% above the upper limit of normal, or significant hyper- or hypocalcemia. Note: Rescreening for certain assessments is permitted as described in the protocol. 5. Known active fungal, bacterial, and / or viral infection including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or COVID-19 virus. A negative COVID-19 test result is required within 5 days prior to first dose of ENPP1-Fc. 6. Known intolerance to ENPP1-Fc or any of its excipients. 7. Unable or unwilling to discontinue the use of any prohibited medication (examples include bisphosphonates, calcimimetics, antacids, systemic corticosteroids, pyrophosphate containing medications) as provided in the protocol. Discontinuation should be undertaken only if considered not detrimental and indicated by the subject's treating physician. 8. Receipt of any other investigational new drug within 5 half-lives of the last dose of the other investigational product or from 4 weeks prior to the first dose of ENPP1-Fc, whichever is longer, or use of an investigational device, through completion of participation in the study 9. Last symptoms from a COVID-19 vaccination within 14 days prior to the first dose of ENPP1-Fc or as described in Inozyme COVID-19 Vaccine Guidance Document. Example 8: Treatment of a Patient Diagnosed with GACI having ABCC6 deficiency ABCC6 deficiency may mask as GACI. GACI is a rare disease occurring in infants and involving extensive arterial calcification (Albright, et al., 2015, Nature Comm.10006). GACI is believed to occur due to a defective ENPP1 protein. Surprisingly, in some instances, GACI Atty. Docket No.4427-12602 phenotype is observed even when the subject has ABCC6 deficiency. Infants with ABCC6 deficiency can be identified by using isolated DNA samples using protocols described in J Med Genet.2007 Oct; 44(10): 621–628. (Mutation detection in the ABCC6 gene and genotype– phenotype analysis in a large international case series affected by pseudoxanthoma elasticum, Ellen G Pfendner, et al) ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC once or twice weekly for a period of time determined by the medical professional. GACI Infant (having ABCC6 deficiency) response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of GACI, and / or using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 9: Treatment of Patient Diagnosed with ARHR2 having ABCC6 deficiency ABCC6 deficiency may mask as symptoms of ARHR2. ARHR2 is a rare skeletal disorder characterized by low levels of plasma PPi and serum phosphate which can result in rickets, repeated fractures of the long bones, rachitic skeletal deformities and impaired growth and development (Ferreira et al 2014, Moran 1975, Rutsch et al 2008). In some infants, ARHR2 phenotype is observed when the subject has ABCC6 deficiency. Infants with ABCC6 deficiency can be identified by following the procedure in Example 4. ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC once or twice weekly for a period of time determined by the medical professional. ARHR2 infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of ARHR2, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 10: Treatment of Patient Diagnosed with Chronic kidney disease (CKD) Pathological calcification can manifest as another disease state referred as CKD. Clinical symptoms of chronic kidney diseases include itching, muscle cramps, nausea, lack of appetite, swelling of feet and ankles, sleeplessness and labored breathing. Chronic kidney disease if left untreated tends to progress into End stage renal disease (ESRD). (Chronic Kidney Disease Diagnosis and Management: A Review, Chen TK, Knicely DH, Grams ME. Chronic Kidney Disease Diagnosis and Management: A Review. JAMA.2019 Oct 1;322(13):1294-1304.) Atty. Docket No.4427-12602 ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC once or twice weekly for a period of time determined by the medical professional. CKD infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of CKD, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 11: Treatment of Patient Diagnosed with Ossification of posterior longitudinal ligament (OPLL) Pathological calcification can manifest as another disease state referred as OPLL. Clinical symptoms and signs caused by OPLL are categorized as: (1) myelopathy, or a spinal cord lesion with motor and sensory disturbance of the upper and lower limbs, spasticity, and bladder dysfunction; (2) cervical radiculopathy, with pain and sensory disturbance of the upper limbs; and (3) axial discomfort, with pain and stiffness around the neck. The most common symptoms in the early stages of OPLL include dysesthesia and tingling sensation in hands, and clumsiness. (Wu JC, Chen YC, Huang WC. Ossification of the Posterior Longitudinal Ligament in Cervical Spine: Prevalence, Management, and Prognosis. Neurospine.2018 Mar;15(1):33- ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. OPLL infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of OPLL, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 12: Treatment of Patient Diagnosed with Hereditary Hypophosphatemic Rickets Pathological calcification can manifest as another disease state referred as Hereditary Hypophosphatemic Rickets (HHR). Clinical symptoms and signs caused by HHR are categorized as: (1) myelopathy, or a spinal cord lesion with motor and sensory disturbance of the upper and lower limbs, spasticity, and bladder dysfunction; (2) cervical radiculopathy, with pain and sensory disturbance of the upper limbs; and (3) axial discomfort, with pain and stiffness around the neck. The most common symptoms of HHR include premature fusion of the skull bones (craniosynostosis) and dental abnormalities. The disorder may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy). In adults, hypophosphatemia is characterized by a softening of the bones known as osteomalacia. (Cho HY, Atty. Docket No.4427-12602 Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res.2005 Aug;58(2):329-33.) ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. HHR infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of HHR, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 13: Treatment of Patient Diagnosed with X-linked hypophosphatemia (XLH) Pathological calcification can manifest as another disease state referred as X-linked hypophosphatemia (XLH). X-linked dominant hypophosphatemic rickets, or X-linked Vitamin D-resistant rickets, is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. (Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res.2011 Jul;26(7):1381-8. doi: 10.1002 / jbmr.340. Epub 2011 May 2. Erratum in: J Bone Miner Res.2015 Feb;30(2):394) ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. XLH infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of XLH, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 14: Treatment of Patient Diagnosed with Autosomal Dominant Hypophosphatemic Rickets (ADHR) Pathological calcification can manifest as another disease state referred as Autosomal Dominant Hypophosphatemic Rickets (ADHR). Clinical symptoms and signs caused by ADHR poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR is characterized by impaired mineralization of bone, rickets and / or osteomalacia, suppressed levels of calcitriol (1, 25-dihydroxyvitamin D3), renal phosphate wasting, and low serum phosphate. Mutations in FGF23 render the protein more stable and uncleavable by proteases resulting in enhanced bioactivity of FGF23. The enhanced Atty. Docket No.4427-12602 activity of FGF23 mutants reduce expression of sodium-phosphate co-transporters, NPT2a and NPT2c, on the apical surface of proximal renal tubule cells, resulting in renal phosphate wasting. (Rowe PS. The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med. 2004 Sep 1;15(5):264-81.) ENPP1-Fc is administered to an infant of the age of 7 days at a selected dose of ENPP1- FC is one of 2.4 mg / kg SC at least once or twice weekly for a period of time determined by the medical professional. ADHR infant response to enzyme replacement is monitored as appropriate, as determined by the medical professional, e.g., by following a reduction in one or more symptoms of ADHR, using guidance provided herein. The following examples, in the context of the entire specification, provide guidance to determine treatment protocols and efficacy. Example 15: Measurement of Plasma Inorganic Pyrophosphate Low plasma PPi levels are a characteristic of ENPP1 Deficiency and are used as an indicator of treatment efficacy. ENPP1-Fc specifically cleaves ATP to generate AMP and PPi. The therapeutic goal of ENPP1 ERT is to normalize extracellular PPi levels and correct clinical abnormalities associated with ENPP1 Deficiency. PPi is measured by obtaining patient plasma samples. Determined PPi data may be used to adjust dose levels. PPi levels may also serve as the primary PD marker for PK / PD analysis. The concentration of Pi and PPi in infants is 1-3 mM and 1-3 µM respectively. Infants with ENPP1 deficiency have PPi under 1 µm, in some cases the PPi level is 967 nm in subjects with ENPP1 deficiency or ABCC6 deficiency. Example 16: Biomarkers Associated with Bone Health In addition to low plasma PPi, ENPP1 deficient infants are characterized biochemically by low serum phosphate, high urine phosphate, low renal TmP / GFR, normal calcium (Ca), low- normal urine Ca, normal 25-hydroxy Vitamin D (25 OH D), low-normal 1,25(OH)2D, high BAP, high intact FGF23, and normal PTH (IOF 2019). Biomarkers that may be used as additional determinants of bone health of a treated patient are set forth in Table 11. Table 11: Clinical Intermediates and Biomarkers Atty. Docket No.4427-12602 Example 17: Efficacy of Treatment with ENPP1-Fc Treatment efficacy may be assessed by measuring plasma PPi as well as measuring other plasma analytes, such as FGF23, Pi, FGF23, Pi, TmP / GFR, serum alkaline phosphatase (ALP), bone-specific ALP (BALP), carboxy terminal cross-linked telopeptide of type I collagen (CTx), and procollagen type 1 N-terminal propeptide (P1NP). These analyte measurements may be used as a PD markers associated with ENPP1 Deficiency to determine the efficacy for ENPP1-FC. Changes in these analytes may be described as changes from baseline and in a time-dependent manner over the course of treatment. Dose linearity of PK and PD parameters also may be assessed. Changes from baseline in plasma PPi levels, FGF23 levels and Urinary phosphorus excretion per creatinine clearance may be analyzed using a test of paired differences to test the null hypothesis that the change from baseline of PPi levels is equal to zero. Example 18: Drug Concentration Measurements In addition, blood samples may be obtained from an infant of the age of 7 days for measurement of ENPP1-FC concentration in plasma and subsequent determination of PK parameters following the first dose (i.e., single dose) and at / after multiple doses (i.e., steady- state). Example 19: Immunogenicity (Anti-drug Antibodies) If desired, immunogenicity to ENPP1-Fc may be measured using anti-drug antibodies (ADA). Immunogenicity testing can utilize a multi-tiered approach; if ADA are detected in the initial screen, a confirmatory test may be run to determine specificity. Samples may also be used to assess and further establish assays for specificity confirmation (i.e., titer) and neutralizing antibodies. Example 20: Pharmacokinetic, Pharmacodynamic, and Exploratory Biomarker Analyses Pharmacokinetic analysis may be performed on the PK population, and PK parameters of ENPP1-FC may be summarized by treatment with descriptive statistics. Dose linearity of PK and PD parameters may also be assessed. PK / PD analyses, immunogenicity analyses; and exploratory biomarker analyses may be determined. Atty. Docket No.4427-12602 Example 21: Additional Determinators of Efficacy Although restoring a normal level of PPi is the primary indicator of efficacy of treatment using NEPP1-Fc, other physical measurements also may be used, if desired to assist in determining treatment efficacy. These include one or more of the following. 1. Radiography and Imaging X-Rays for Skeletal Severity. Standard X-rays may be obtained to detect rachitic skeletal deformities. Obtain X-rays may be obtained, for example, on the wrists and knees. DEXA Scan. DEXA scans may be used to evaluate changes in bone density. Positron Emission Tomography – Computed Tomography. Baseline Na18F- PET / HRpQCT (or HR-CT) may be a full body scan done within 1 month of first dose of ENPP1- FC to measure calcification of arteries and organs and skeletal abnormalities at baseline and for future interventional assessments. The Na18F-PET measures bone turnover as well as microcalcification of the arteries. High-resolution quantitative computed tomography (HRQCT) or HR-CT can determine bone microstructure at the non-dominant distal radius and tibia. Standard bone geometric parameters are calculated. Doppler Echocardiogram. A baseline echocardiogram may be obtained within 3 days prior to a first dose of ENPP1-FC. Doppler echo may be used to measure heart function [LVEF, blood flow] calcification of heart and valves, and arterial stiffness. Optical Coherence Tomography. Optical coherence tomography may be used to visualize neointimal proliferation. Peripheral Arterial Tonometry. Peripheral arterial tonometry (PAT) may be used to assess digital pulse wave amplitude (PWA), which corresponds to digital volume variation. Renal Ultrasound. Renal ultrasound may be used, for example, within 1 week of starting ENPP1-FC, to measure renal calcification. Range of Motion. Range of Motion may be assessed using a goniometer, an instrument that tests the angle of joints and measures the degree of movement at a joint. The stationary arm of the goniometer is aligned with the specified bony landmark on the stationary body segment, and the moving arm of the goniometer is aligned with the specified bony landmark of the limb that is moving. The fulcrum of the goniometer is specified for each motion measured using axis of motion and bony landmarks. Range of motion may be assessed for one or more of the following: shoulder abduction, shoulder flexion, elbow flexion, elbow extension, hip abduction, hip flexion, hip extension, and knee extension. Atty. Docket No.4427-12602 2. Hearing Testing. Moderate hearing loss has been associated with ARHR2 (Brachet et al 2014, Steichen-Gersdorf et al 2015). Baseline hearing may be determined by one or more of: Physical exam and otoscopy, Immittance audiometry (commonly called tympanometry), Pure Tone Audiometry (PTA) with frequencies up to 8 kHz if possible. (If there is a PTA threshold of >15dB, the subject should also undergo bone conduction testing.), High Frequency Audiometry (HFA), with frequencies up to 16 kHz. 3. Clinician Global Impression Scales. The Clinical Global Impression (CGI-S) scales were developed for use in National Institute of Mental Health-sponsored clinical studies to provide a brief, stand-alone assessment of the clinician's view of the infant's global functioning prior to and after initiating a study medication (Guy 1976). The CGI provides an overall clinician-determined summary measure that considers all available information, including knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. The CGI-S may be administered before and / or during treatment at the discretion of the healthcare provider and provides a global assessment of change using a seven-point scale ranging from -3 (severe worsening) to +3 (significant improvement). The Table below shows the scale and the corresponding impression which is an indicator of overall health of the patient when compared to a base line such as that of a healthy person or health of a patient prior to dosage regimen. (See Guy, W. Clinical global impressions (CGI) scale. Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Association.2000:100-102.) 4. Caregiver Global Impression Scales. The Caregiver Global Impression of Status may be administered to the patient’s caregiver before and / or during treatment at the discretion of the healthcare provider. The Caregiver Global Impression of Change provides a global assessment of change using a seven-point scale ranging from -3 (severe worsening) to +3 (significant improvement). Atty. Docket No.4427-12602 5. Western Ontario and McMaster University Osteoarthritis Index. The WOMAC is a patient-reported outcome used to assess activities of daily living, functional mobility, gait, general health, pain, and quality of life in patients with hip or knee pain (www.sralab.org). The assessment consists of 24-items and takes approximately 12 minutes to administer. The WOMAC may be administered before and / or during treatment at the discretion of the healthcare provider. The assessment may be completed by the subject without assistance. Example 22: Treatment of Infants with ENPP1 deficiency by administering 2.4 mg of ENPP1- Fc per kg body weight of infant subjects. A 3-month-old infant diagnosed with Generalized Arterial Calcification of Infancy (GACI) at 19 days of age was found to have bi-allelic mutations in the ENPP1 gene. Upon presentation, the patient exhibited extensive arterial calcification, systemic hypertension, a reduced left ventricular ejection fraction (LVEF) of 40%, and signs of congestive heart failure. Treatment with INZ-701, a recombinant ENPP1-Fc fusion protein, was initiated at 3 months of age, with a gradually escalating dosing regimen that reached a target dose of 2.4 mg / kg administered weekly by 8.5 months of age. Before reaching the target dose, the patient’s pre-dose plasma pyrophosphate (PPi) level was measured at 58 nM, markedly below the normal reference range of 1002–2169 nM (Khursigara et al., Effects of food, fasting, and exercise on plasma pyrophosphate levels and ENPP1 activity in healthy adults. Bone.2023 Jun;171). Following the 2.4 mg / kg dose, plasma PPi levels rose significantly, reaching 750 nM at 6 hours post-dose and further increasing to 971 nM at 24 hours post-dose (Figure 7), demonstrating a robust pharmacodynamic response. Despite mild levels of anti-drug antibody (ADA), which reduced the effective amount of ENPP1-Fc available for increasing PPi levels, the therapy still elevated PPi to near-normal concentrations. No adverse events were found during or after administration of ENPP1-Fc. Although not bound by theory, it is believed that in some cases infants can exhibit a pronounced ADA response due to their developing immune systems and maternal antibody interactions. Their immune regulation is still maturing, making biologic drugs such as ENPP1-Fc more likely to be perceived as foreign. Additionally, maternal IgG antibodies transferred in utero can influence drug recognition, sometimes exacerbating immune responses. A second infant, diagnosed with GACI at birth and also carrying bi-allelic ENPP1 mutations, began treatment with INZ-701 at 2 months of age. This patient presented with arterial calcification, a baseline LVEF of 52%, and additional calcifications in joints and soft tissues. The INZ-701 dose was escalated to 2.4 mg / kg weekly by 11 months of age. Prior to this dose, plasma PPi levels were below the limit of quantification. However, four hours after administration, PPi levels increased to 215 nM. At the subsequent dose, levels rose from 72 nM pre-dose to 198 nM eight hours post-dose (Figure 8). The second infant exhibited moderate levels of ADA, which significantly reduced the effective ENPP1-Fc available for PPi elevation. Atty. Docket No.4427-12602 While PPi levels increased toward the normal range, they remained lower than those observed in the first infant. No adverse events were found during or after administration of ENPP1-Fc in the second infant as well. Despite the moderate ADA levels reducing ENPP1-Fc availability, the therapy remained physiologically effective in clearing pathological calcification in the second infant. Surprisingly, imaging via low-dose CT scan revealed complete resolution of arterial calcification across multiple vascular territories, including the abdominal arteries, renal arteries, carotid arteries, abdominal aorta, and pulmonary artery outflow tract (Figure 9). This unexpected finding underscores the potent efficacy of ENPP1-Fc in reversing vascular calcification, even in the presence of ADA-related drug neutralization. The ability of INZ-701 to achieve complete calcification clearance despite moderate ADA interference suggests that even partial levels of ENPP1-Fc is sufficient for substantial clinical benefit. These findings demonstrate that weekly administration of ENPP1-Fc (INZ-701) at a dose of 2.4 mg / kg is both safe and effective for infants with GACI. The treatment significantly increases plasma PPi levels and can lead to complete resolution of pathological vascular and soft tissue calcification. REFERENCES Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, et al. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun.2015 Dec 1;6:10006. Chanchlani R, Nemer P, Sinha R, Nemer L, Krishnappa V, Sochett E, et al. An Overview of Rickets in Children. Kidney Int Rep.2020;5:980-90. Cheng Z, O'Brien K, Howe J, Sullivan C, Schrier D, Lynch A, et al. INZ-701 prevents ectopic tissue calcification and restores bone architecture and growth in ENPP1-deficient mice. J Bone Miner Res.2021;36(8):1594-604. Chunn LM, Bissonnette J, Heinrich SV, Mercurio SA, Kiel MJ, Rutsch F, Ferreira CR. Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature Orphanet J Rare Disreview and population databases. Orphanet J Rare Dis.2022;17(1):421. Ferreira CR, Kintzinger K, Hackbarth ME, Botschen U, Nitschke Y, Mughal MZ, et al. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. J Bone Miner Res.2021b;36(11):2193-202. Hoppner J, Kornak U, Sinningen K, Rutsch F, Oheim R, Grasemann C. Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) due to ENPP1-deficiency. Bone.2021;153:116111. Atty. Docket No.4427-12602 Khan T, Sinkevicius KW, Vong S, Avakian A, Leavitt MC, Malanson H, 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):dmm035691. Mackenzie NC, Huesa C, Rutsch F, MacRae VE. New insights into NPP1 function: lessons from clinical and animal studies. Bone.2012 Nov;51(5):961-8. Martinez-Millana A, Hulst J, M.,, Boon M, Witters P, Fernandez-Llatas C, Asseiceira I, al. e. Optimisation of children z-score calculation based on new statistical techniques. PLoS One. 2018;13(12):e208362. NCI. Common Terminology Criteria for Adverse Events V5.0 (CTCAE). Published: November 27, 2017.2017; Available from: https: / / ctep.cancer.gov / protocoldevelopment / electronic_applications / docs / ctcae_v5_quick_refere nce_8.5x11.pdf. Orriss IR, Arnett TR, Russell RG. Pyrophosphate: a key inhibitor of mineralisation. Curr Opin Pharmacol.2016 Jun;28:57-68. Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008 Dec;1(2):133-40. Scheinman SJ, Carpenter T. Hereditary hypophosphatemic rickets and tumor-induced osteomalacia. UpToDate.2023:1-44. Strensiq [package insert]. Alexion Pharmaceuticals Inc. U.S. Food and Drug AdministrationRevised June 2020; Available from: https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 125513s018lbl.pdf. . ADDITIONAL EMBODIMENTS 1. A method for preventing the progression of or reducing vascular calcification in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce vascular calcification in the subject. 2. A method for preventing the progression of or reducing pathological calcification in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce pathological calcification in the subject. Atty. Docket No.4427-12602 3. A method for preventing the progression of or reducing tissue calcification in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject 4. A method for preventing the progression of or reducing pathological ossification in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. 5. A method for increasing circulating pyrophosphate (PPi) in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby increase circulating PPi in the subject. 6. A method for increasing pyrophosphatase activity in a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby increase circulating PPi in the subject. 7. A method for ameliorating one or more symptoms of ENPP1 Deficiency in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby ameliorate one or more symptoms of ENPP1 Deficiency in the subject. 8. A method for treating a subject with ENPP1 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby treat the subject. 9. A method for preventing the progression of or reducing vascular calcification in a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce vascular calcification in the subject. 10. A method for preventing the progression of or reducing pathological calcification in a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce pathological calcification in the subject. 11. A method for preventing the progression of or reducing tissue calcification in a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. 12. A method for preventing the progression of or reducing pathological ossification in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about Atty. Docket No.4427-12602 2.4mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. 13. A method for increasing circulating pyrophosphate (PPi) in a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram bodyweight of of the subject to thereby increase circulating PPi in the subject. 14. A method for increasing pyrophosphatase activity in a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby increase circulating PPi in the subject. 15. A method for ameliorating one or more symptoms of pathological calcification in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby ameliorate one or more symptoms of pathological calcification in the subject. 16. A method for treating a subject with pathological calcification, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby treat the subject. 17. A method for preventing the progression of or reducing vascular calcification in a subject with ABCC6 Deficiency or ABCC6 deficient subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce vascular calcification in the subject. 18. A method for preventing the progression of or reducing pathological calcification in a subject with ABCC6 Deficiency or ABCC6 deficient subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce pathological calcification in the subject. 19. A method for preventing the progression of or reducing tissue calcification in a subject with ABCC6 Deficiency or ABCC6 deficient subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce tissue calcification in the subject. 20. A method for preventing the progression of or reducing pathological ossification in a subject with ABCC6 Deficiency or ABCC6 deficient subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby prevent the progression of or reduce pathological ossification in the subject. Atty. Docket No.4427-12602 21. A method for increasing circulating pyrophosphate (PPi) in a subject with ABCC6 Deficiency or ABCC6 deficient subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby increase circulating Ppi in the subject. 22. A method for increasing pyrophosphatase activity in a ABCC6 deficient subject or a subject with ABCC6 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby increase pyrophosphatase activity in the subject. 23. A method for ameliorating one or more symptoms of ABCC6 deficient subject or ABCC6 Deficiency in a subject, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby ameliorate one or more symptoms of ABCC6 Deficiency in the subject. 24. A method for treating a ABCC6 deficient subject or a subject with ABCC6 Deficiency, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby treat the subject. 25. A method of treating a subject afflicted with one or more symptoms of PXE, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby treat said subject. 26. A method of treating a subject who is an infant and exhibits abnormal vascular calcification and / or one or more symptoms of ENPP1 deficiency, and / or GACI, the method comprising: administering to the subject an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the subject to thereby treat said subject. 27. The method of any one of innovations 1-26, wherein the dose is about 2.4 mg per kilogram of bodyweight of the subject. 28. The method of any one of innovations 1-27, wherein said subject is human. 29. The method of innovation 28, wherein said subject is an infant under the age of 1. 30. The method of any one of innovations 1-29, wherein the ENPP1 agent is administered at least one time per week. 31. The method of any one of innovations 1-30, wherein the ENPP1 agent is administered at least two times per week. 32. The method of any one of innovations 1-30, wherein the ENPP1 agent is administered to the subject at least one or two times per week following an initial dose. 33. The method of any one of innovations 1-32, wherein the ENPP1 agent is administered subcutaneously. Atty. Docket No.4427-12602 34. The method of any one of innovations 1-33, wherein the ENPP1 agent is administered by a care giver. 35. The method of any one of innovations 1-34, wherein the ENPP1 agent is administered under a dosing regimen comprising: (a) an initial dose of about 2.4 mg per kilogram of the subject and (b) about seven days after the initial dose, once or twice weekly administration of maintenance doses of the ENPP1 agent of about 2.4 mg per kilogram of bodyweight of the subject. 36. The method of innovation 35, wherein the initial dose and the maintenance doses are the same. 37. The method of any one of innovations 1-34, wherein the ENPP1 agent comprises the catalytic domain of ENPP1. 38. The method of any one of innovations 1-37, wherein the ENPP1 agent comprises the nuclease domain of ENPP1. 39. The method of any one of innovations 1-38, wherein the ENPP1 agent comprises the extracellular domain of ENPP1. 40. The method of any one of innovations 1-39, wherein the ENPP1 agent comprises a heterologous moiety. 41. The method of innovation 40, wherein the heterologous moiety is a polypeptide. 42. The method of innovation 40 or 41, wherein the heterologous moiety increases the circulating half-life of the ENPP1 agent relative to the circulating half-life of the ENPP1 agent lacking the heterologous moiety. 43. The method of innovation 41 or 42, wherein the heterologous moiety comprises the Fc region of an immunoglobulin molecule. 44. The method of innovation 43, wherein the immunoglobulin molecule is a human immunoglobulin molecule. 45. The method of innovation 43 or 44, wherein the immunoglobulin molecule is an IgG1. 46. The method of innovation 41 or 42, wherein the heterologous moiety comprises albumin. 47. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1 [ENPP1 ECD]. 48. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises amino acid residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:3. 49. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO:5. Atty. Docket No.4427-12602 50. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO:3. 51. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO:2. 52. The method of any one of innovations 1-35, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO:3 or 4 or 5. 53. The method of any one of innovations 1-35, wherein the subject has or is suspected of having generalized arterial calcification of infancy (GACI). 54. The method of any one of innovations 1-35, wherein the subject has or is suspected of having autosomal recessive hypophosphatemic rickets type 2 (ARHR2). 55. The method of any one of innovations 1-35, wherein the pharmaceutical composition contains as the sole active ingredient around 2.4 mg of ENPP1-Fc per kg of weight of the subject. 56. The method of anyone of innovations 1-35, wherein the subject has been treated with one or more statins and / or one or more proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors prior to said administration of said ENPP1 agent. 57. The method of anyone of innovations 1-35, wherein the subject has been treated with a selected dose or selected doses of one or more statins and / or one or more PCSK9 inhibitors for 3 or more years prior administration of said ENPP1 agent. 58. The method of anyone of innovations 1-35, wherein the subject has not been diagnosed with a malignancy prior to said administration of said ENPP1 agent. 59. The method of anyone of innovations 1-35, wherein the subject has not been diagnosed with a malignancy prior to said administration of said ENPP1 agent. 60. The method of innovation 58, wherein said malignancy excludes non-melanoma skin cancers and cervical carcinoma in situ. 61. The method of any one of innovations 1-52, wherein the subject has or is suspected of having Pseudoxanthoma elasticum (PXE). 62. The method of any one of innovations 1-52, wherein the subject exhibits symptoms similar to a person having autosomal recessive hypophosphatemic rickets type 2 (ARHR2) or generalized arterial calcification of infancy (GACI). 63. The method of any one of innovations 1-35, wherein the pharmaceutical composition contains as the sole active ingredient around 2.4 mg / kg of weight of subject. 64. The method of any one of innovations 1-52, wherein the subject has or is suspected of having one or more of kidney and bladder stones, dental pulp stones, gall stones, salivary gland Atty. Docket No.4427-12602 stones, chronic calculous prostatitis, testicular microliths, calcification in hemodialysis patients, atherosclerosis, malacoplakia, scleroderma (systemic sclerosis), calcinosis cutis, calcific aortic stenosis, calcific tendonitis, synovitis and arthritis, diffuse interstitial skeletal hyperostosis, juvenile dermatomyositis, Generalized Arterial Calcification of Infancy (GACI), Ossification of the Posterior Longitudinal Ligament (OPLL), autosomal hypophosphatemic rickets (ARHR2), osteoarthritis, calcification of atherosclerotic plaques, Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), Pseudoxanthoma elasticum (PXE), ankylosing spondylitis, hardening of the arteries, calciphylaxis, and systemic lupus erythematosus. 65. The method of any one of innovations 1-52, wherein said subject exhibits calcification of soft connective tissues. 66. The method of innovation 65, wherein said subject exhibits accumulation of deposits of calcium and other minerals (mineralization) in elastic fibers of connective tissues. 67. The method of innovation 65, wherein said subject exhibits calcification in the eyes, cardiovascular system, and / or skin. 68. The method of innovation 67, wherein said subject exhibits narrowing of the arteries and / or arteriosclerosis. 69. The method of treating a subject according to any one of innovations 1-52, wherein said subject exhibits ectopic calcification and / or narrow of blood vessels in the lower extremities, and / or claudication. 70. The method of treating a subject according to any one of innovations 1-52, wherein said subject exhibits abnormalit...

Claims

Atty. Docket No.4427-12602 CLAIMS 1. A method for preventing the progression of or reducing pathological calcification in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce pathological calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of an age greater than 30 minutes and less than 12 months.

2. A method for preventing the progression of or reducing pathological ossification in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby prevent the progression of or reduce tissue calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

3. A method for increasing circulating pyrophosphate (PPi) in an infant with ENPP1 Deficiency, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant to thereby increase circulating PPi in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

4. A method for preventing the progression of or reducing pathological calcification in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby prevent the progression of or reduce pathological calcification in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

5. A method for preventing the progression of or reducing pathological ossification in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby prevent the progression of or reduce pathological ossification in the infant, wherein said infant is under the age of 1 year or wherein an infant is of age greater than 30 minutes and less than 12 months.

6. A method for increasing circulating pyrophosphate (PPi) in an infant with ABCC6 Deficiency or ABCC6 deficient infant, the method comprising: administering to the infant an ENPP1 agent at a dose of about 2.4 mg per kilogram of bodyweight of the infant, to thereby increase circulating PPi in the infant, wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

7. A syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 2.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.Atty. Docket No.4427-12602 8. A syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

9. A syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months, and wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

10. A syringe pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.6 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months, and wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

11. The syringe of any one of claims 7-8, wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

12. The syringe of any one of claims 7-8, wherein said pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70 mM sucrose, about 32 mM (D) mannitol, and about 0.02% w / v polysorbate 20.

13. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 2.4 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

14. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.2 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

15. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 1.8 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months and wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mMAtty. Docket No.4427-12602 calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

16. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 0.6 mg per kilogram of body weight of an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months and wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

17. The vial of any one of claims 13-14, wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

18. The vial of any one of claims 13-14, wherein said pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70 mM sucrose, about 32 mM (D) mannitol, and about 0.02% w / v polysorbate 20.

19. The method of any one of claims 1-6, wherein the ENPP1 agent is administered subcutaneously.

20. The method of any one of claims 1-6, wherein the ENPP1 agent is administered once a week at a dosage of 2.4 mg of ENPP1 agent per kg of body weight of said infant to achieve a total dose of 2.4 mg of ENPP1 agent per kg of body weight of said infant.

21. The method of any one of claims 1-6, wherein the ENPP1 agent is administered twice a week at a dosage of 1.2 mg of ENPP1 agent per kg of body weight of said infant to achieve a total dose of 2.4 mg of ENPP1 agent per kg of body weight of said infant.

22. The method of any one of claims 1-6, wherein the ENPP1 agent is administered thrice a week at a dosage of 0.8 mg of ENPP1 agent per kg of body weight of said infant to achieve a total dose of 2.4 mg of ENPP1 agent per kg of body weight of said infant.

23. The method of any one of claims 1-6, wherein the ENPP1 agent is administered four times a week at a dosage of 0.6 mg of ENPP1 agent per kg of body weight of said infant to achieve a total dose of 2.4 mg of ENPP1 agent per kg of body weight of said infant.

24. The method of any one of claims 1-6, wherein the ENPP1 agent is administered six times a week at a dosage of 0.2 mg of ENPP1 agent per kg of body weight of said infant to achieve a total dose of 2.4 mg of ENPP1 agent per kg of body weight of said infant.

25. The method of any one of claims 1-6, wherein the ENPP1 agent comprises a heterologous moiety, and wherein said heterologous moiety increases the circulating half-life of the ENPP1 agent relative to the circulating half-life of the ENPP1 agent lacking the heterologous moiety.Atty. Docket No.4427-12602 26. The method of any one of claims 1-6, wherein the ENPP1 agent comprises a heterologous moiety and wherein said heterologous moiety comprises the Fc region of an immunoglobulin molecule.

27. The method of any one of claims 1-6, wherein the ENPP1 agent comprises amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1 or residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:

3.

28. The method of any one of claims 1-6, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO: 2 or 3 or 4 or 5.

29. The method of any one of claims 1-6, wherein the infant has or is suspected of having one of generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), Hypopyrophosphatemia and Pseudoxanthoma elasticum (PXE).

30. The method of anyone of claims 1-6, wherein the infant has been treated with one or more statins and / or one or more proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors prior to said administration of said ENPP1 agent.

31. The method of anyone of claims 1-6, wherein the infant has been treated with a selected dose or selected doses of one or more statins and / or one or more PCSK9 inhibitors prior administration of said ENPP1 agent.

32. The method of anyone of claims 1-6, wherein the infant has not been diagnosed with a malignancy prior to said administration of said ENPP1 agent.

33. The method of any one of claims 1-6, wherein the infant has or is suspected of having one or more of kidney and bladder stones, dental pulp stones, gall stones, salivary gland stones, chronic calculous prostatitis, testicular microliths, calcification in hemodialysis patients, atherosclerosis, malacoplakia, scleroderma (systemic sclerosis), calcinosis cutis, calcific aortic stenosis, calcific tendonitis, synovitis and arthritis, diffuse interstitial skeletal hyperostosis, juvenile dermatomyositis, Generalized Arterial Calcification of Infancy (GACI), Ossification of the Posterior Longitudinal Ligament (OPLL), autosomal hypophosphatemic rickets (ARHR2), osteoarthritis, calcification of atherosclerotic plaques, Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD), Pseudoxanthoma elasticum (PXE), ankylosing spondylitis, hardening of the arteries, calciphylaxis, and systemic lupus erythematosus.

34. The method of any one of claims 1-6, wherein said infant exhibits one or more of calcification of soft connective tissues, accumulation of deposits of calcium and other minerals (mineralization) in elastic fibers of connective tissues, calcification in the eyes, calcification of cardiovascular system, calcification of skin. narrowing of the arteries, arteriosclerosis. ectopic calcification, narrowing of blood vessels in the lower extremities, claudication, abnormal pigmentation of cells of the retina, angioid streaks, abnormalities in the elastic membrane beneath the retina, choroidal neovascularization, visual impairment, vision loss, and blindness.Atty. Docket No.4427-12602 35. The method of any of one of claims 1 or 4, wherein said pathological calcification comprises vascular calcification or tissue calcification.

36. The method of any one of claims 1-6 or 19-35, wherein said infant has or is suspected of having GACI or ARHR2.

37. The method of any one of claims 1-6 or 19-35, wherein said infant has or is suspected of having PXE.

38. The method of any one of claims 1-6 or 19-35, wherein said infant is not an adult.

39. The method of any one of claims 1-6 or 19-35, wherein said infant is not a child of age greater than one but less than 13.

40. The method of any one of claims 1-6 or 19-35, wherein said infant is 1-7 days old, 7-14 days old, 14-21 days old, 21-28 days old, 28-35 days old, 35-42 days old, 42-49 days old, 49-56 days old, 56-63 days old, 63+70 days old, 70-77 days old, 77-84 days old, 84-91 days old, 91-98 days old, 98-105 days old, 105-112 days old, 112-119 days old, 119-126 days old, 126-133 days old, 133-140 days old, 140-147 days old, 147-154 days old, 154-161 days old, 161-168 days old, 175-182 days old, 182-189 days old, 196-203 days old, 203-210 days old, 210-217 days old, 217-224 days old, 224-231 days old, 231-238 days old, 238-245 days old, 245-252 days old, 252-259 days old, 259-266 days old, 266-273 days old, 273-280 days old, 280-287 days old, 287-294 days old, 294-301 days old, 301-308 days old, 308-315 days old, 315 -322 days old, 322-329 days old, 329-336 days old, 336-343 days old, 343-350 days old, 350-357 days old, or 357-364 days old.

41. The method of claim 32, wherein said malignancy excludes non-melanoma skin cancers and cervical carcinoma in situ.

42. The method of any one of claims 1-6, wherein the ENPP1 agent is administered once a week or twice a week or once biweekly or once a month.

43. The method of any one of claims 1-6, wherein the ENPP1 agent upon administration raises the plasma pyrophosphate (PPi) levels in said infant when compared to the PPi levels present in said infant before said administration.

44. The method of any one of claims 1-6, wherein the ENPP1 agent upon administration raises the plasma pyrophosphate (PPi) levels in said infant from less than 1µm to greater than 1µm.

45. The method of any one of claims 1-6, wherein the ENPP1 agent upon administration raises the plasma pyrophosphate levels (PPi) in said infant from less than 100 nm to greater than 900 nm.

46. The method of any one of claims 1-6, wherein the ENPP1 agent upon administration reduces or completely removes the calcification in one or more of abdominal artery, renal artery, pulmonary artery and carotid artery.Atty. Docket No.4427-12602 47. The syringe of anyone of claims 7-10, wherein the ENPP1 polypeptide comprises amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1 or residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:

3.

48. The syringe of anyone of claims 7-10, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO: 2 or 3 or 4 or 5.

49. The vial of anyone of claims 13-16, wherein the ENPP1 polypeptide comprises amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1 or residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:

3.

50. The vial of anyone of claims 13-16, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO: 2 or 3 or 4 or 5.

51. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount ranging from 1-200 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

52. A vial pre-filled with a pharmaceutical composition comprising a ENPP1 polypeptide, wherein the ENPP1 polypeptide is present in an amount of 200 mg / ml or 175 mg / ml or 150 mg / ml or 125 mg / ml or 100 mg / ml or 75 mg / ml or 50 mg / ml or 25 mg / ml for administration to an infant having pathological calcification and wherein said infant is under the age of 1 year or wherein the infant is of age greater than 30 minutes and less than 12 months.

53. The vial of any one of claims 51-52, wherein said pharmaceutical composition further comprises about 20 mM citrate at about pH 6.3, about 2 mM calcium chloride, about 175 mM sucrose, about 82 mM (D) mannitol, and about 0.05% w / v polysorbate 20.

54. The vial of any one of claims 51-52, wherein said pharmaceutical composition further comprises about 8 mM citrate at about pH 6.3, about 0.8 mM calcium chloride, about 70 mM sucrose, about 32 mM (D) mannitol, and about 0.02% w / v polysorbate 20.

55. The vial of anyone of claims 51-52, wherein the ENPP1 polypeptide comprises amino acid residues 99 (PSCAKE) to 925 (QED) of SEQ ID NO:1 or residues 1 (FTAGLKPSCAKE) to 833 (QED) of SEQ ID NO:

3.

56. The vial of anyone of claims 51-52, wherein the ENPP1 agent comprises the amino acid sequence depicted in SEQ ID NO: 2 or 3 or 4 or 5.

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