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)

Q&A With Katherine L Madson PhD, MD, Pediatric Rheumatologist at the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospital for Children.

What is Hypophosphatasia?

Dr. Madson: Hypophosphatasia is a genetic metabolic bone disease. The people are born with a mutation in one of their genes and they do not make an enzyme that we all have called alkaline phosphatase. The disease can be apparent in utero, during the first 6 months of life, early childhood, or as an adult in your 40s or 50s. The most severe is during in utero and the least severe is as an adult. So, it is a spectrum of severity.

When we are talking about severity, what are some of the symptoms that you would typically see in a person that has this disease?

Dr. Madson: The important thing is that the severity that appears at any of the stages is sort of characteristic of that period. If you get it later in life, you do not regress. The babies in utero do not develop skeletons. If they do not die in utero, it used to be that they would die at birth because they did not have ribs, they did not have bones. You cannot breathe if you do not have ribs. Then, infantile, during the first 6 months of life when it showed up was the next most severe, and in those kids their disease could show up at any point in that first 6 months; usually as failure to thrive, meaning they quit growing. They would lose weight. They got into breathing difficulties; again, because their ribs were not very well formed. They were not rolling over, moving their hands, their arms because their bones were not very good and 50% of those infants would die. In childhood, usually the first sign is that the kids lose their teeth anywhere from a month after they erupt to a couple of years afterwards. Children are not supposed to lose teeth until they are 6 or 7 years of age. These kids lose the entire tooth. It is very long and there are no absorption markers on the tooth. It almost could look like an upside down fang if you would. Usually dentists will pick it up at that point, but then the parents may say that the kids did not walk at the appropriate time; they are not jumping; they are not running, so they are getting some signs of muscle weakness and they will complain of bone pain. But, they can be very mild; just have the tooth loss and a little bit of x-ray changes, but no developmental issues. Then with the adults, usually it is broken bones in the feet and initially they will heal, but after you break it 2 or 3 times it does not heal and the characteristic is these non-healing fractures in the feet. Somebody will look at blood work as they are trying to evaluate this and go, your enzyme level is low. They may have gone 40 to 50 years without ever knowing this. Obviously it is much less severe for adults than it is for the in utero infant or the newborn infant.

Are they more likely to die if they are younger?

Dr. Madson: Yes. That is not to say that adults and children do not have complaints, but just the severity is less the older they are.

How has this been treated in the past?

Dr. Madson: Symptomatically. What could you do to help take care of bone pain and that was usually rest, Tylenol, ibuprofen, for the children for instance. The babies might be placed on a ventilator to breath for them. It could be very difficult trying to wean them from the ventilator. There really was not a treatment.

Tell me about the new treatment.

Dr. Madson: It is an enzyme that was made by a company formerly known as Enobia and they had figured out how to use a marker that would go directly to the bone and they made the enzyme that these kids and adults are missing. Attached it to the marker and either injected by vein or given by skin injection and it goes to the bone and starts working., The babies were the first ones that were allowed to use it because obviously if you are newborn and chances are very good you are going to die, the FDA was more willing to let those babies receive this untested drug and they did well. They grew bones. Many of those kids came off the ventilator within months. There is 1 of the children that has a Facebook page, and she started preschool, running, jumping, skipping, doing all age appropriate things and had difficulty breathing when she was first born.

How long does it typically talk to see results?

Dr. Madson: With this study, our endpoints were 6 month intervals although we were seeing the kids more often. Children that have bones, but have alterations in the bones, we could see changes after about 12 weeks. Definite changes at 6 months. The infants that had some skeleton that was not very good started making bones and you could see that within weeks and a few months. If they were born and you were hard pressed to see a skeleton on x-ray, it took much longer. You really had to start at scratch to build those bones.

Was that an outcome that you expected or was that a surprise?

Dr. Madson: They had done work in mice as the experimental model and they knew that they could create a mouse that did not have the alkaline phosphatase enzyme. When they were injected, they could see bones grow in mice and they could see that mice that had the perinatal form were surviving and were growing and were acting like normal mice. They were pretty sure it would work, but going from mice to humans is a leap. That is why they were not cavalier in using it in the infants, but most parents were willing to take the risk if it meant their child could possibly benefit rather than die. But everybody had to know it was experimental and be willing to participate in that.

How does that feel for you as a doctor?

Dr. Madson: We dealt with kids that were 5 years to 12 years and it was exciting to watch them come back in and especially during the first 6 months of the trial. They would come in and show us how far they could jump or “Look at how fast I can walk.” “Look at me run.” And, we honestly had to remind ourselves that we did not create the enzyme. We were just the physicians giving it to the kids and supervising that because there was just this feeling of awe to see how well they were doing.

What is next for the treatment?