Premium
Prolonged survival and phenotypic correction of Akp2 − / − hypophosphatasia mice by lentiviral gene therapy
Author(s) -
Yamamoto Seiko,
Orimo Hideo,
Matsumoto Tae,
Iijima Osamu,
Narisawa Sonoko,
Maeda Takahide,
Millán José Luis,
Shimada Takashi
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.201
Subject(s) - hypophosphatasia , alkaline phosphatase , rickets , osteomalacia , medicine , genetic enhancement , endocrinology , knockout mouse , biology , gene , enzyme , vitamin d and neurology , genetics , biochemistry , receptor
Hypophosphatasia (HPP) is an inherited systemic skeletal disease caused by mutations in the gene encoding the tissue‐nonspecific alkaline phosphatase ( TNALP ) isozyme. The clinical severity of HPP varies widely, with symptoms including rickets and osteomalacia. TNALP knockout ( Akp2 − / − ) mice phenotypically mimic the severe infantile form of HPP; that is, TNALP ‐deficient mice are born with a normal appearance but die by 20 days of age owing to growth failure, hypomineralization, and epileptic seizures. In this study, a lentiviral vector expressing a bone‐targeted form of TNALP was injected into the jugular vein of newborn Akp2 − / − mice. We found that alkaline phosphatase activity in the plasma of treated Akp2 − / − mice increased and remained at high levels throughout the life of the animals. The treated Akp2 − / − mice survived for more than 10 months and demonstrated normal physical activity and a healthy appearance. Epileptic seizures were completely inhibited in the treated Akp2 − / − mice, and X‐ray examination of the skeleton showed that mineralization was significantly improved by the gene therapy. These results show that severe infantile HPP in TNALP knockout mice can be treated with a single injection of lentiviral vector during the neonatal period. © 2011 American Society for Bone and Mineral Research.