title: Successful gene therapy in utero for lethal murine hypophosphatasia.
abstract: Hypophosphatasia (HPP), caused by mutations in the gene ALPL encoding tissue-nonspecific alkaline phosphatase (TNALP), is an inherited systemic skeletal disease characterized by mineralization defects of bones and teeth. The clinical severity of HPP varies widely, from a lethal perinatal form to mild odontohypophosphatasia showing only dental manifestations. HPP model mice (Akp2(-/-)) phenotypically mimic the severe infantile form of human HPP; they appear normal at birth but die by 2 weeks of age because of growth failure, hypomineralization, and epileptic seizures. In the present study, we investigated the feasibility of fetal gene therapy using the lethal HPP model mice. On day 15 of gestation, the fetuses of HPP model mice underwent transuterine intraperitoneal injection of adeno-associated virus serotype 9 (AAV9) expressing bone-targeted TNALP. Treated and delivered mice showed normal weight gain and seizure-free survival for at least 8 weeks. Vector sequence was detected in systemic organs including bone at 14 days of age. ALP activities in plasma and bone were consistently high. Enhanced mineralization was demonstrated on X-ray images of the chest and forepaw. Our data clearly demonstrate that systemic injection of AAV9 in utero is an effective strategy for the treatment of lethal HPP mice. Fetal gene therapy may be an important choice after prenatal diagnosis of life-threatening HPP.
authors: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, 113-8602 Japan.
authors: Hanako
authors: H
authors: Sugano
authors: Tae
authors: T
authors: Matsumoto
authors: Koichi
authors: K
authors: Miyake
authors: Atsushi
authors: A
authors: Watanabe
authors: Osamu
authors: O
authors: Iijima
authors: Makoto
authors: M
authors: Migita
authors: Sonoko
authors: S
authors: Narisawa
authors: José Luis
authors: JL
authors: Millán
authors: Yoshitaka
authors: Y
authors: Fukunaga
authors: Takashi
authors: T
authors: Shimada
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D046128:Fetal Therapies; D015316:Genetic Therapy; D007014:Hypophosphatasia / Q000235:genetics / Q000628:therapy*; D051379:Mice; D011247:Pregnancy; D014599:Uterus
chemical_list: C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase