Enzyme Replacement Therapy for Murine Hypophosphatasia

Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss‐of‐function mutation(s) within the gene that encodes the tissue‐nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PP i ), an inhibitor of mineralization, and pyridoxal 5′‐phosphate (PLP), a co‐factor form of vitamin B 6 . Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B 6 ‐dependent seizures. There is no established medical treatment. Materials and Methods: Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one‐step purification and a deca‐aspartate sequence (D 10 ) for targeting to mineralizing tissue (sALP‐FcD 10 ). TNALP‐null mice ( Akp2 −/− ), an excellent model for infantile HPP, were treated from birth using sALP‐FcD 10 . Short‐term and long‐term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP‐FcD 10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP‐FcD 10 activity, calcium, PP i , and pyridoxal, as well as skeletal and dental manifestations using radiography, μCT, and histomorphometry. Results: Akp2 −/− mice receiving high‐dose sALP‐FcD 10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PP i , and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Conclusions: Enzyme replacement using a bone‐targeted, recombinant form of human TNALP prevents infantile HPP in Akp2 −/− mice.