Enzyme-Replacement Therapy in Life-Threatening Hypophosphatasia

• Published in: The New England journal of medicine Vol. 366; no. 10; pp. 904 - 913
• Main Authors: Whyte, Michael P, Greenberg, Cheryl R, Salman, Nada J, Bober, Michael B, McAlister, William H, Wenkert, Deborah, Van Sickle, Bradley J, Simmons, Jill H, Edgar, Terence S, Bauer, Martin L, Hamdan, Mohamed A, Bishop, Nick, Lutz, Richard E, McGinn, Mairead, Craig, Stanley, Moore, Jean N, Taylor, John W, Cleveland, Robert H, Cranley, William R, Lim, Ruth, Thacher, Tom D, Mayhew, Jill E, Downs, Matthew, Millán, José Luis, Skrinar, Alison M, Crine, Philippe, Landy, Hal
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 08.03.2012
• Subjects: Age; Alkaline phosphatase; Alkaline Phosphatase - administration & dosage; Alkaline Phosphatase - pharmacology; Alkaline Phosphatase - therapeutic use; Biological and medical sciences; Biological Availability; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone diseases; Calcification; Calcification (ectopic); Calcium (dietary); Child, Preschool; Children; Cognitive ability; Collaboration; Dietary supplements; Enzyme Replacement Therapy - adverse effects; Enzymes; Errors of metabolism; Female; General aspects; Humans; Hypocalcemia; Hypophosphatasia; Hypophosphatasia - complications; Hypophosphatasia - drug therapy; Immunoglobulin G - administration & dosage; Immunoglobulin G - pharmacology; Immunoglobulin G - therapeutic use; Infant; Infant, Newborn; Infants; Infusions, Intravenous; Injections, Subcutaneous - adverse effects; Male; Medical sciences; Metabolic diseases; Metabolism; Mineralization; Miscellaneous hereditary metabolic disorders; Osteomalacia; Parathyroid; Parathyroid hormone; Patients; Pharmacodynamics; Pharmacokinetics; Phosphatase; Plasma levels; Radiography; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Respiratory function; Rickets; Rickets - diagnostic imaging; Rickets - drug therapy; Rickets - etiology; Statistical analysis; Treatment Outcome; Life-threatening; Alkaline phosphatase; Replacement therapy; Enzyme; Critically ill; Phosphoric monoester hydrolases; Metabolic diseases; Esterases; Enzymopathy; Hypophosphatasia; Genetic disease; Medicine; Hydrolases
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMoa1106173

In this study of perinatal and infantile hypophosphatasia, patients received ENB-0040, a bone-targeted, recombinant, human tissue-nonspecific isozyme of alkaline phosphatase that is lacking in this disease. Rickets healed, and developmental milestones and pulmonary function improved. Hypophosphatasia is the inborn error of metabolism that is characterized by low serum alkaline-phosphatase activity from loss-of-function mutations, typically missense, within the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). 1 Natural substrates of TNSALP that accumulate in hypophosphatasia include inorganic pyrophosphate, 2 an inhibitor of mineralization, 3 and pyridoxal 5′-phosphate (PLP), the principal circulating form of vitamin B 6 . 4 High extracellular levels of inorganic pyrophosphate block hydroxyapatite crystal growth 3 , 5 and cause rickets or osteomalacia. Hypercalcemia and hyperphosphatemia can develop in severely affected patients. 1 The deranged vitamin B 6 metabolism shows that TNSALP functions as a cell-surface enzyme 6 and explains . . .