Key discoveries in the history of HPP include the 1923 discovery of alkaline phosphatase and the development of the hypothesis that this A molecule that catalyzes or triggers biochemical reactions.enzyme plays an important role in The process by which the body uses minerals to build bone structure.bone mineralization; the 1948 naming and first official case report of the disease; and later, the association of HPP with phosphocompound substrates, which was central to understanding the disease.
1923:
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Robert Robison discovers alkaline phosphatase (ALP)15 and offers the hypothesis that it is critical for bone mineralization, particularly the liberation of inorganic phosphate (Pi) for hydroxyapatite crystal formation16.
16 Robison R. (1932) The Significance of Phosphoric Esters in Metabolism. New York University Press, New York.
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1936:
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Bruce Chown describes two cases of baby sisters with renal A softening of bones in children leading to fractures and deformity, which is predominantly caused by a vitamin D deficiency.rickets who die at three and six months of age17.
17 Chown B. (1936) Renal rickets and dwarfism: A pituitary disease. Br J Surg 23(91):552-566.
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1948:
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Canadian pediatrician John C. Rathbun creates the name A rare, inherited, and sometimes fatal metabolic bone disease characterized by poor bone mineralization and profound skeletal defects.hypophosphatasia for a case report of a baby boy with subnormal ALP tissue activity who died from acquired rickets complicated by A chronic neurological disorder characterized by recurrent episodes of unprovoked seizures.epilepsy 18.
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1955:
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Raised concentrations of phosphoethanolamine (PEA) are identified in urine, providing a second A hormone, enzyme, antibody, or other biochemical substance that is detected in bodily fluids or tissues that may serve as a sign of disease or abnormality.biochemical marker for HPP19, 20, 21.
19 Fraser D., Yendt E.R. (1955) Metabolic abnormalities in hypophosphatasia. Am J Dis Child, 90:552-554.
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20Fraser D., Yendt E.R., Christie F.H.E. (1955) Metabolic abnormalities in hypophosphatasia. Lancet, 1: 286.
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21McCance R.A., Morrison A.B., Dent C.E. (1955) The excretion of phosphoethanolamine and hypophosphatasia. Lancet, 1:131.
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1965 & 1971:
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Elevated levels of Regulates certain intracellular functions and extracellular crystal formation.inorganic pyrophosphate (Ppi) in the urine22 and The fluid portion of blood, in which blood cells are suspended.plasma 23 of HPP patients are identified and point to the cause of defective bone mineralization, as PPi increasingly is proven to inhibit this process24.
22 Russell R.G.G.(1965) Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet, 2:461- 464.
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24 Heinonen J.K. (2001)Biological Role of Inorganic Pyrophosphate. Kluwer Academic Publishers, Norwell, MA.
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1982:
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A molecule that catalyzes or triggers biochemical reactions.Enzyme replacement therapy in HPP patient attempted by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease25.
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1985:
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High plasma concentrations of The active form of vitamin B6.pyridoxal 5’-phosphate (PLP) are found in HPP patients. This, in conjunction with knowledge about vitamin B6 metabolism, reveals an An enzyme that works outside of the cell that secretes it.ectoenzyme function for TNSALP, clarifying how these three phosphocompounds could accumulate extracellularly26.
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1986:
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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 127.
27 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.
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2003:
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First Cells or tissues that are reimplanted in the same individual from which they came.autologous bone marrow transplant performed in an HPP patient28.
28 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.
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2005:
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Enobia begins Research done prior to a clinical study.preclinical studies using bone targeted, recombinant human ALP. |
2008:
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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 bone-targeted, recombinant human ALP. |
