Rescue of severe infantile hypophosphatasia mice by AAV-mediated sustained expression of soluble alkaline phosphatase

Tae Matsumoto, Koichi Miyake, Seiko Yamamoto, Hideo Orimo, Noriko Miyake, Yuko Odagaki, Kumi Adachi, Osamu Iijima, Sonoko Narisawa, José Luis Millán, Yoshitaka Fukunaga, Takashi Shimada

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


Hypophosphatasia (HPP) is an inherited disease caused by a deficiency of tissue-nonspecific alkaline phosphatase (TNALP). The major symptom of human HPP is hypomineralization, rickets, or osteomalacia, although the clinical severity is highly variable. The phenotypes of TNALP knockout (Akp2 -/-) mice mimic those of the severe infantile form of HPP. Akp2 -/- mice appear normal at birth, but they develop growth failure, epileptic seizures, and hypomineralization and die by 20 days of age. Previously, we have shown that the phenotype of Akp2 -/- mice can be prevented by enzyme replacement of bone-targeted TNALP in which deca-aspartates are linked to the C-terminus of soluble TNALP (TNALP-D10). In the present study, we evaluated the therapeutic effects of adeno-associated virus serotype 8 (AAV8) vectors that express various forms of TNALP, including TNALP-D10, soluble TNALP tagged with the Flag epitopes (TNALP-F), and native glycosylphosphatidylinositol-anchored TNALP (TNALP-N). A single intravenous injection of 5×10 10 vector genomes of AAV8-TNALP-D10 into Akp2 -/- mice at day 1 resulted in prolonged survival and phenotypic correction. When AAV8-TNALP-F was injected into neonatal Akp2 -/- mice, they also survived without epileptic seizures. Interestingly, survival effects were observed in some animals treated with AAV8-TNALP-N. All surviving Akp2 -/- mice showed a healthy appearance and a normal activity with mature bone mineralization on X-rays. These results suggest that sustained alkaline phosphatase activity in plasma is essential and sufficient for the rescue of Akp2 -/- mice. AAV8-mediated systemic gene therapy appears to be an effective treatment for the infantile form of human HPP.

Original languageEnglish
Pages (from-to)1355-1364
Number of pages10
JournalHuman Gene Therapy
Issue number11
Publication statusPublished - 1 Nov 2011
Externally publishedYes


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