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Infantile Hypophosphatasia: Transplantation Therapy Trial Using Bone Fragments and Cultured Osteoblasts

Pediatric Research Institute (R.A.C.), Cardinal Glennon Children’s Hospital, St. Louis, Missouri 63110; Center for Metabolic Bone Disease and Molecular Research (D.W., S.M., M.P.W.), Shriners Hospitals for Children, St. Louis, Missouri 63131; All Children’s Hospital (S.A.P., A.S.), University of South Florida, St. Petersburg, Florida 33713; Department of Chemistry (S.P.C.), Indiana University-Purdue University, Fort Wayne, Indiana 46805; Mallinckrodt Institute of Radiology (W.H.M.), Washington University School of Medicine at St. Louis Children’s Hospital, and Division of Bone and Mineral Diseases (S.M., M.P.W.), Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. Michael P. Whyte, Shriners Hospitals for Children, 2001 South Lindbergh Boulevard, St. Louis, Missouri 63131. E-mail: mwhyte{at}shrinenet.org.

Background: Hypophosphatasia (HPP) is a rare, heritable, metabolic bone disease due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. The infantile form features severe rickets often causing death in the first year of life from respiratory complications. There is no established medical treatment. In 1997, an 8-month-old girl with worsening and life-threatening infantile HPP improved considerably after marrow cell transplantation.

Objective: Our aim was to better understand and to advance these encouraging transplantation results.

Design: In 1999, based on emerging mouse transplantation models involving implanted donor bone fragments as well as osteoblast-like cells cultured from bone, we treated a 9-month-old girl suffering a similar course of infantile HPP.

Results: Four months later, radiographs demonstrated improved skeletal mineralization. Twenty months later, PCR analysis of adherent cells cultured from recipient bone suggested the presence of small amounts of paternal (donor) DNA despite the absence of hematopoietic engraftment. This patient, now 8 yr old (7 yr after transplantation), is active and growing, and has the clinical phenotype of the more mild, childhood form of HPP.

Conclusions: Cumulative experience suggests that, after immune tolerance, donor bone fragments and marrow may provide precursor cells for distribution and engraftment in the skeletal microenvironment in HPP patients to form tissue-nonspecific isoenzyme of alkaline phosphatase-replete osteoblasts that can improve mineralization.