Key Discoveries in the History of HPP

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Key discoveries in the history of HPP include the 1923 discovery of alkaline phosphatase and the development of the hypothesis that this enzyme plays an important role in 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:

 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.

1936:

 Bruce Chown describes two cases of baby sisters with renal rickets who die at three and six months of age17.

1948:

 Canadian pediatrician John C. Rathbun creates the name hypophosphatasia for a case report of a baby boy with subnormal ALP tissue activity who died from acquired rickets complicated by epilepsy 18.

1955:

 Raised concentrations of phosphoethanolamine (PEA) are identified in urine, providing a second biochemical marker for HPP19, 20, 21.

1965 & 1971:

 Elevated levels of inorganic pyrophosphate (Ppi) in the urine22 and 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.

1982:

 Enzyme replacement therapy in HPP patient attempted by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease25.

1985:

 High plasma concentrations of pyridoxal 5’-phosphate (PLP) are found in HPP patients. This, in conjunction with knowledge about vitamin B6 metabolism, reveals an ectoenzyme function for TNSALP, clarifying how these three phosphocompounds could accumulate extracellularly26.

1986:

 Gene coding TNSALP is mapped to chromosome 127.

2003:

 First autologous bone marrow transplant performed in an HPP patient28.

2005:

 Enobia begins preclinical studies using bone targeted, recombinant human ALP.

2008:

 Enobia begins clinical trials investigating bone-targeted, recombinant human ALP.