Prolonged survival and phenotypic correction of Akp2(-/-) hypophosphatasia mice by lentiviral gene therapy.
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.
Yamamoto
Seiko
S
Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
Orimo
Hideo
H
Matsumoto
Tae
T
Iijima
Osamu
O
Narisawa
Sonoko
S
Maeda
Takahide
T
Millán
José Luis
JL
Shimada
Takashi
T
D000469:Alkaline Phosphatase / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D005528:Foot / Q000000981:diagnostic imaging; D015316:Genetic Therapy; D007014:Hypophosphatasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D010641:Phenotype; D011859:Radiography; D016019:Survival Analysis; D013977:Tibia / Q000201:enzymology / Q000473:pathology
C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase