Enzyme replacement therapy for murine hypophosphatasia.
BACKGROUND
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.


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, microCT, 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.
Millán
José Luis
JL
Burnham Institute for Medical Research, La Jolla, California 92037, USA. millan@burnham.org
Narisawa
Sonoko
S
Lemire
Isabelle
I
Loisel
Thomas P
TP
Boileau
Guy
G
Leonard
Pierre
P
Gramatikova
Svetlana
S
Terkeltaub
Robert
R
Camacho
Nancy Pleshko
NP
McKee
Marc D
MD
Crine
Philippe
P
Whyte
Michael P
MP
D000469:Alkaline Phosphatase / Q000172:deficiency / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001691:Biological Therapy; D006801:Humans; D007014:Hypophosphatasia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011859:Radiography; D013997:Time Factors
D000469:Alkaline Phosphatase