Prolonged Survival and Phenotypic Correction of Akp2(-/-) Hypophosphatasia Mice by Lentiviral Gene Therapy

作者：Yamamoto Seiko; Orimo Hideo; Matsumoto Tae; Iijima Osamu; Narisawa Sonoko; Maeda Takahide; Millan Jose Luis; Shimada Takashi^*

来源：Journal of Bone and Mineral Research, 2011, 26(1): 135-142.

DOI：10.1002/jbmr.201

• ALKALINE PHOSPHATASE
• LENTIVIRAL VECTOR
• ENZYME REPLACEMENT
• EPILEPSY
• CALCIFICATION

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.

• 出版日期2011-1