title: Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector.
abstract: Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2 (-/-) ) mice, which mimic the phenotype of the severe infantile form of HPP, can be treated by intravenous injection of a recombinant adeno-associated virus (rAAV) expressing bone-targeted TNALP with deca-aspartates at the C-terminus (TNALP-D10) driven by the tissue-nonspecific CAG promoter. To develop a safer and more clinically applicable transduction strategy for HPP gene therapy, we constructed a self-complementary type 8 AAV (scAAV8) vector that expresses TNALP-D10 via the muscle creatine kinase (MCK) promoter (scAAV8-MCK-TNALP-D10) and examined the efficacy of muscle-directed gene therapy. When scAAV8-MCK-TNALP-D10 was injected into the bilateral quadriceps of neonatal Akp2 (-/-) mice, the treated mice grew well and survived for more than 3 months, with a healthy appearance and normal locomotion. Improved bone architecture, but limited elongation of the long bone, was demonstrated on X-ray images. Micro-CT analysis showed hypomineralization and abnormal architecture of the trabecular bone in the epiphysis. These results suggest that rAAV-mediated, muscle-specific expression of TNALP-D10 represents a safe and practical option to treat the severe infantile form of HPP.
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Nakamura-Takahashi
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan; Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hirai
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Iijima
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nitahara-Kasahara
authors.affiliation: Department of Dental Materials Science, Tokyo Dental College , Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Anatomy, Tokyo Dental College , Tokyo, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Anatomy, Tokyo Dental College , Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Abe
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Prebys Medical Discovery Institute , La Jolla, California, USA.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Narisawa
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Prebys Medical Discovery Institute , La Jolla, California, USA.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Millán
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School , Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada