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

Overview

Journal J Bone Miner Res

Publisher Oxford University Press

Date 2010 Aug 6

PMID 20687159

Citations 30

Authors

Seiko Yamamoto

Hideo Orimo

Tae Matsumoto

Osamu Iijima

Sonoko Narisawa

Takahide Maeda

Jose Luis Millan

Takashi Shimada

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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