Fixing Bad Bones -- Research Summary

BACKGROUND: Hypophosphatasia is an inherited, rare bone disease whose clinical symptoms are highly variable, ranging from a profound lack of mineralization of bone with death occurring prior to delivery up to early loss of teeth in adulthood as the only sign. Still other affected individuals may have the characteristic biochemical abnormality but no outward clinical signs of the disorder. Hypophosphatasia is due to consistently low levels of an important enzyme in the body, alkaline phosphatase. (SOURCES: Healthline, Gale Encyclopedia of Public Health)

THE PROBLEM:
Alkaline phosphatase (ALP) is present in nearly all plants and animals. There are at least four different genes known to encode different forms of ALP in humans. Hypophosphatasia is due to a deficiency of the form of ALP that is particularly abundant in the liver, bones, and kidneys. This is often referred to as the tissue non-specific form of ALP, or TNSALP. This form of alkaline phosphatase is important in the mineralization, or hardening, of the bones of the skeleton as well as the teeth. Thus, abnormalities in either the production or function of this enzyme have a direct effect on the formation and strength of these parts of the body. In general, the more severe forms of hypophosphatasia are associated with lower serum TNSALP activity for that individual's age. (SOURCES: Healthline, Gale Encyclopedia of Public Health)

TREATMENT:
Doctors at Washington University School of Medicine in St. Louis, working with Shriners Hospital for Children and other institutions, have identified a promising new treatment. The experimental treatment used in the study, ENB-0040, is a manufactured form of normal alkaline phosphatase, but enhanced so that it is targeted to bone.

After six months of treatment, most patients showed substantial healing of rickets. After one year, six patients were breathing unaided. Of the nine patients who completed one year of treatment, all made progress, sometimes significant, in motor development. One progressed to moving all limbs against gravity, one to sitting unsupported, two could crawl, one pulled to standing, and two started taking steps. Of the two older children who could only sit, both progressed to walking after a year of treatment.

Treating these patients by giving them normal alkaline phosphatase is not a new idea. More than two decades ago, Michael P. Whyte, MD, professor of medicine, of pediatrics and of genetics at Washington University School of Medicine in St. Louis and his colleagues attempted to treat patients with hypophosphatasia by giving them blood plasma with excess alkaline phosphatase. That unsuccessful study showed that raising alkaline phosphatase levels in the blood was not enough. More recently, Whyte’s industry collaborators have provided the missing link: Adding a short protein chain that adheres to bone allowed the alkaline phosphatase to be targeted to the skeleton.

Paving the way for this human study, Whyte and his colleagues then showed that the targeting chain worked well in a mouse model of severe hypophosphatasia, restoring normal life span to mice, as long as they received daily injections of ENB-0040 starting at birth. The nine patients who completed one year of treatment continue to receive therapy and are now participating in an extension study. For more information about clinical trials recruiting patients with hypophosphatasia, visit clinicaltrials.gov./ (SOURCE: Washington University) MORE

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