Marrow Cell Transplantation for Infantile Hypophosphatasia

Abstract

An 8-month-old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T-cell-depleted, haplo-identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor. Three months later, she was clinically improved, with considerable healing of rickets and generalized skeletal remineralization. However, 6 months post-transplantation, worsening skeletal disease recurred, with partial return of host hematopoiesis. At the age of 21 months, without additional chemotherapy or immunosuppressive treatment, she received a boost of donor marrow cells expanded ex vivo to enrich for stromal cells. Significant, prolonged clinical and radiographic improvement followed soon after. Nevertheless, biochemical features of hypophosphatasia have remained unchanged to date. Skeletal biopsy specimens were not performed. Now, at 6 years of age, she is intelligent and ambulatory but remains small. Among several hypotheses for our patient's survival and progress, the most plausible seems to be the

Transplantable marrow osteoprogenitors engraft in discrete saturable sites in the marrow microenvironment

“…In our pilot study, we demonstrated that marrow osteoprogenitors can engraft in bone giving rise to donor-derived osteoblasts, modify the microscopic structure of the bone, and promote clinical benefits for children with OI, suggesting a contribution to osteogenesis [13,14]. Subsequent to our initial report, other investigators demonstrated that hypophosphatasia, another genetic disorder of bone, may also be treated with BMT [15,16], independently validating our original findings.…”

Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers

“…11,12 Bone marrow transplantation has been reported to treat several patients with hypophosphatasia. 13 However, a method must be developed that improves the survival of donor mesenchymal cells in patients. Likewise, other congenital enzyme defect disorders, such as Hurler or Hunter disease, recombinant enzyme replacement therapy is being attempted in hypophosphatasia.…”

Outcome of Perinatal Hypophosphatasia in Manitoba Mennonites: A Retrospective Cohort Analysis

“…Two unrelated patients with worsening infantile HPP received marrow cell transplantations and survived a likely lethal outcome (Cahill et al 2007;Whyte et al 2003). Now, enzyme replacement therapy for severe HPP using human recombinant bone-targeted alkaline phosphatase provides promise for improved outcome (Whyte et al 2012).…”