Hypophosphatasia (
HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific
isozyme of
alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult
HPP. Other types include odonto
HPP and perinatal benign. Babies with the perinatal/infantile forms of
HPP often die with severe
rickets and
respiratory insufficiency and sometimes
hypercalcemia and
vitamin B6-responsive
seizures. The primary biochemical defect in
HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic
pyrophosphate (PPi), a potent calcification inhibitor. To-date, the management of
HPP has been essentially symptomatic or orthopedic. However,
enzyme replacement therapy with
mineral-targeting TNAP (sALP-FcD10, also known as ENB-0040 or
asfotase alfa) has shown promising results in a mouse model of
HPP (Alpl-/- mice). Administration of
mineral-targeting TNAP from birth increased survival and prevented the
seizures,
rickets, as well as all the
tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe
HPP. Clinical trials using
mineral-targeting TNAP in children 3 years of age or younger with life-threatening
HPP was associated with healing of the skeletal manifestations of
HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued
asfotase alfa therapy, with more than 3 years of treatment in some children.
Enzyme replacement therapy with
asfotase alfa has to-date been successful in patients with life-threatening
HPP.