Biochemical and Morphological Effects of Human Hepatic Alkaline Phosphatase in a Neonate with Hypophosphatasia

Abstract

Acta Paediatr Scand Suppl 360: 154, 1989. Enzyme replacement-therapy for a severely affected premature boy (birthweight: 2 380 g, GA: 36 weeks) with hypophosphatasia was attempted by infusions of purified human hepatic alkaline phosphatase. Treatment (1.2 IU/kg/min) started at age three weeks and was repeated in weekly intervals until age 10 weeks, when the child died. Samples of alkaline phosphatase were diluted with 10 ml of physiological saline and infused over 30 min via an umbilical arterial catheter. No toxic or allergic side effects were observed. Serum alkaline phosphatase activity increased from 3 IU/L before treatment to a maximum level of 195 IU/L with a half-life time between 37 and 62 hours. Urinary excretion of phosphoethanolamine decreased during therapy from a maximal level of 9.5 to 5.5 pmol/mg creatinine (normal: <0.4 pmol/mg creatinine). Calcium, phosphorus, parathormone and 1,25-diOH vitamin D levels were within normal range. Sequential radiographic studies showed no improvement of bone mineralization. Bone morphology was studied by light and electron microscopy before treatment and post mortem. The borderline between mineralized and unmineralized matrix was more distinct after treatment and on the electron microscopical level initial spots of mineralization were more frequent between the collagen fibrils compared to the biopsy specimen before treatment. In contrast to previous studies however, only woven and bundle bone structures were studied from the tibia1 crest, where the lack of osteoblast-like cells upon the newly formed osteoid matrix was prominent.

Hypophosphatasia: an overview of the disease and its treatment

“…The early attempts consisted in the intravenous administration of normal plasma, ALP-enriched plasma from patients with Paget bone disease, purified human liver ALP, or purified human placental ALP in infants with severe HPP, but were not successful [113][114][115].…”

Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl−/− mice by administration of soluble (non-targeted) chimeric alkaline phosphatase

“…Attempted enzyme replacement therapy (ERT) using intravenous (IV) infusions of ALP-rich plasma from Paget’s bone disease patients, purified human liver ALP, or purified human placental ALP failed to rescue severely affected infants [44,48–50]. From these studies, it was concluded that TNAP activity might need to be directed to the skeleton rather than simply enhanced in the circulation in order to prevent or reverse the pathophysiology of HPP [5,46].…”

Enhancement of drug delivery to bone: Characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide

“…The results of ERT, however, with intravenous infusion of plasma ALP or purified liver ALP in patients with hypophosphatasia have been disappointing [36][37][38][39][40]. Recently, one report suggested that continuous delivery of high dose of TNSALP to bone would be needed to induce physiological bone mineralization [41].…”