Drs Lemire, Loisel, Leonard, and Crine are employees of Enobia Pharma. Drs Millán, McKee, Boileau, and Whyte are consultants for Enobia Pharma. All other authors state that they have no conflicts of interest.
Enzyme Replacement Therapy for Murine Hypophosphatasia†
Article first published online: 17 DEC 2007
Copyright © 2008 ASBMR
Journal of Bone and Mineral Research
Volume 23, Issue 6, pages 777–787, June 2008
How to Cite
Millán, J. L., Narisawa, S., Lemire, I., Loisel, T. P., Boileau, G., Leonard, P., Gramatikova, S., Terkeltaub, R., Camacho, N. P., McKee, M. D., Crine, P. and Whyte, M. P. (2008), Enzyme Replacement Therapy for Murine Hypophosphatasia. J Bone Miner Res, 23: 777–787. doi: 10.1359/jbmr.071213
Presented in part at the 5th International Alkaline Phosphatase Symposium, May 16–19, 2007, Huningue, France; the 17th Scientific Meeting, International Bone and Mineral Society, June 24–29, 2007, Montreal, Canada; and the 29th Annual Meeting of the American Society for Bone and Mineral Research, September 16–19, 2007, Honolulu, Hawaii, USA.
- Issue published online: 4 DEC 2009
- Article first published online: 17 DEC 2007
- Manuscript Accepted: 14 DEC 2007
- Manuscript Revised: 5 DEC 2007
- Manuscript Received: 7 SEP 2007
- alkaline phosphatase;
Introduction: 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 (PPi), an inhibitor of mineralization, and pyridoxal 5′-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-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 (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2−/−), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, μCT, and histomorphometry.
Results:Akp2−/− mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, 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.