PMID- 22133046
OWN - NLM
STAT- MEDLINE
DCOM- 20130624
LR  - 20220202
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Print)
IS  - 1043-0342 (Linking)
VI  - 23
IP  - 4
DP  - 2012 Apr
TI  - Successful gene therapy in utero for lethal murine hypophosphatasia.
PG  - 399-406
LID - 10.1089/hum.2011.148 [doi]
AB  - 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.
FAU - Sugano, Hanako
AU  - Sugano H
AD  - Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, 
      113-8602 Japan.
FAU - Matsumoto, Tae
AU  - Matsumoto T
FAU - Miyake, Koichi
AU  - Miyake K
FAU - Watanabe, Atsushi
AU  - Watanabe A
FAU - Iijima, Osamu
AU  - Iijima O
FAU - Migita, Makoto
AU  - Migita M
FAU - Narisawa, Sonoko
AU  - Narisawa S
FAU - Millan, Jose Luis
AU  - Millan JL
FAU - Fukunaga, Yoshitaka
AU  - Fukunaga Y
FAU - Shimada, Takashi
AU  - Shimada T
LA  - eng
GR  - R01 DE012889/DE/NIDCR NIH HHS/United States
GR  - DE12889/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120126
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - EC 3.1.3.1 (ALPL protein, mouse)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
SB  - IM
MH  - Alkaline Phosphatase/genetics
MH  - Animals
MH  - Disease Models, Animal
MH  - Feasibility Studies
MH  - Female
MH  - *Fetal Therapies
MH  - Genetic Therapy
MH  - Hypophosphatasia/genetics/*therapy
MH  - Mice
MH  - Pregnancy
MH  - Uterus
PMC - PMC3327603
EDAT- 2011/12/03 06:00
MHDA- 2013/06/26 06:00
PMCR- 2013/04/01
CRDT- 2011/12/03 06:00
PHST- 2011/12/03 06:00 [entrez]
PHST- 2011/12/03 06:00 [pubmed]
PHST- 2013/06/26 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - 10.1089/hum.2011.148 [pii]
AID - 10.1089/hum.2011.148 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2012 Apr;23(4):399-406. doi: 10.1089/hum.2011.148. Epub 2012 Jan 
      26.