Key Discoveries in Hypophosphatasia

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1923:	Robert Robison discovers alkaline phosphatase¹ and develops the hypothesis that this A molecule that catalyzes or triggers biochemical reactions.enzyme is critical for The process by which the body uses minerals to build bone structure.bone mineralization.² ¹ Robison R. (1923) The possible significance of hexosephosphoric esters in The process of bone formation.ossification. Biochem J, 17:286 – 293. close ² Robison R. (1932) The Significance of Phosphoric Esters in Metabolism. New York University Press, New York. close
1936:	A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency.rickets (a kidney dysfunction which causes soft bones) who die at three and six months of age.³ ³ Chown B. (1936) Renal rickets and dwarfism: A pituitary disease. Br J Surg 23(91):552-566. close
1948:	Canadian pediatrician John C. Rathbun names the disease "A rare, inherited, and sometimes fatal metabolic bone disease characterized by poor bone mineralization and profound skeletal defects.hypophosphatasia" (HPP) following the first official case report.⁴ ⁴ Rathbun J.C. (1948) A rare, inherited, and sometimes fatal metabolic bone disease characterized by poor bone mineralization and profound skeletal defects.Hypophosphatasia, a new developmental anomaly. Am J Dis Child, 75:822- 831. close
1955:	Elevated level of phosphoethanolamine (PEA) in urine of patients proves to be a useful marker for HPP.⁵^,⁶^,⁷ This marker is still used for clinical testing today. ⁵ Fraser D., Yendt E.R. (1955) Metabolic abnormalities in hypophosphatasia. Am J Dis Child, 90:552-554. close ⁶Fraser D., Yendt E.R., Christie F.H.E. (1955) Metabolic abnormalities in hypophosphatasia. Lancet, 1: 286. close ⁷McCance R.A., Morrison A.B., Dent C.E. (1955) The excretion of phosphoethanolamine and hypophosphatasia. Lancet, 1:131. close
1965 & 1971:	Elevated levels of Regulates certain intracellular functions and extracellular crystal formation.inorganic pyrophosphate (Ppi) in the urine⁸ and blood⁹ of patients proves to be a useful marker for HPP, and is still used for clinical testing today. This observation also leads researchers to believe that defective bone mineralization is the cause of HPP.¹⁰ ⁸ Russell R.G.G.(1965) Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet, 2:461- 464. close ⁹ Russell R.G., Bisaz S., Donath A., Morgan D.B., and Fleisch H. (1971) Regulates certain intracellular functions and extracellular crystal formation.Inorganic pyrophosphate in The fluid portion of blood, in which blood cells are suspended.plasma in normal persons and in patients with hypophosphatasia, A genetic bone disorder typically caused by a deficiency of Type-I collagen that results in fragile bones. Also known as brittle bone disease.osteogenesis imperfecta, and other disorders of bone. J Clin Invest, 50:961-969. close ¹⁰ Heinonen J.K. (2001)Biological Role of Inorganic Pyrophosphate. Kluwer Academic Publishers, Norwell, MA. close
1982:	Enzyme replacement therapy in an HPP patient is attempted by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease.¹¹ ¹¹ Whyte M.P., Valdes R. Jr., Ryan L.M., McAlister W.H. (1982) Infantile hypophosphatasia: A medical treatment that replaces an enzyme in patients who either lack or have a deficient form of the particular enzyme.enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease. J Peds, 101(3):379-386. close
1985:	Elevated levels of The active form of vitamin B₆.pyridoxal 5’-phosphate (PLP) are found in HPP patients.¹² This marker is still used for clinical testing today. ¹² Whyte M.P., Vrabel L.A. (1985) Infantile hypophosphatasia: The biological unit of heredity that is made up of a DNA sequence, occupies a precise location (locus) on a chromosome, and contains instructions for the production of a particular protein.genetic complimentation analyses with skin fibroblast heterokaryons suggest a defect(s) at a single gene locus. Clin Res, 33: 332A. close
1986:	The biological unit of heredity that is made up of a DNA sequence, occupies a precise location (locus) on a chromosome, and contains instructions for the production of a particular protein.Gene coding TNSALP is mapped to The organized structure of DNA and proteins found in the cell nucleus. Chromosomes come in pairs, and a normal human cell contains 46 chromosomes.chromosome 1.¹³ ¹³ Swallow D.M. (1986) Mapping of the gene coding for the human liver/bone/kidney isozyme of alkaline phosphatase to chromosome 1. Ann Hum Genet, 50(3):229-235. close
2003:	First Cells or tissues that are reimplanted in the same individual from which they came.autologous bone marrow transplant is performed in an HPP patient.¹⁴ ¹⁴ Whyte M.P., Kurtzberg J., McAlister W.H., Mumm S., Podgornik M.N., Coburn S.P., Ryan L.M., Miller C.R., Gottesman G.S., Smith A.K., Douville J., Waters-Pick B., Armstrong R.D., Martin P.L. (2003) Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 18(4):624-636. close
2005:	Enobia begins Research done prior to a clinical study.preclinical studies of ENB-0040.
2008:	Enobia begins A research study that uses consenting human subjects to test the safety and efficacy of new therapeutic interventions and diagnostic tests.clinical trials investigating ENB-0040 in infants and adults with HPP.