Rescue of Severe Infantile Hypophosphatasia Mice by AAV-Mediated Sustained Expression of Soluble Alkaline Phosphatase

Matsumoto, Tae; Miyake, Keisuke; Yamamoto, Setsu; Orimo, Hideo; Miyake, Noriko; Odagaki, Yuko; Adachi, Kumi; Iijima, Osamu; Narisawa, Sonoko; Millán, José Luis; Fukunaga, Yoshitaka; Shimada, Takashi

doi:10.1089/hum.2010.210

Cited by 41 publications

(60 citation statements)

References 43 publications

(56 reference statements)

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“…This distribution pattern was similar to that obtained after neonatal intravenous injection of AAV8 vector (Matsumoto et al, 2011). On the other hand, after fetal intraperitoneal injection, AAV9 vector was widely distributed to all organs examined except the gonads.…”

Section: Figsupporting

confidence: 83%

“…Furthermore, mounting evidence indicates that a continuous supply of soluble TNALP from the circulation might be sufficient to improve mineralization. Indeed, our previous studies showed that systemic injection of lentiviral vector or AAV8 vector harboring either mineral-targeting TNALP or soluble nontargeted TNALP into neonatal mice resulted in sustained expression of TNALP in plasma and successful treatment of HPP, although transduction into bone was low (Yamamoto et al, 2010;Matsumoto et al, 2011). Our present study demonstrates high ALP activity in the bones of treated mice.…”

Section: Discussionsupporting

confidence: 48%

“…The AAV vector plasmid carrying cDNA for TNALP-D10 was described previously (Matsumoto et al, 2011). Recombinant AAV serotype 9 (AAV9) vector was generated by the triple transfection method (Salvetti et al, 1998) and purified as described previously (Hermens et al, 1999;Miyake et al, 2011).…”

Section: Construction and Preparation Of Recombinant Adeno-associatedmentioning

confidence: 99%

“…Another important possibility for the treatment of HPP is gene therapy. We have demonstrated that a single injection of either lentiviral or adeno-associated viral (AAV) vector expressing TNALP-D10 into postnatal HPP mice resulted in prolonged seizure-free survival and phenotypic correction (Yamamoto et al, 2010;Matsumoto et al, 2011). This gene therapy approach is referred to as viral vectormediated ERT, and it is more practical than classical ERT, which requires repeated injections.…”

Section: Introductionmentioning

confidence: 99%

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Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia

et al. 2012

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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.

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Section: Figsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 48%

Section: Construction and Preparation Of Recombinant Adeno-associatedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia

et al. 2012

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“…14 Taking a different approach to treating HPP, we demonstrated that a single intravenous or intraperitoneal injection of a lentiviral or adeno-associated viral (AAV) vector encoding bone-targeted TNALP in which D 10 was linked adjacent to the C-terminus of soluble TNALP (TNALP-D 10 ) resulted in sustained expression of TNALP-D 10 and prevention of the disease phenotype in Akp2 -/-mice. [17][18][19] Viral vectormediated ERT should be more practical and economical than classic ERT, which requires repeated injection of purified recombinant enzyme. There are several concerns with this in vivo gene therapy, however, including the risk of inadvertent germline gene transfer 20,21 and induction of immune responses to the viral vector peptide or transgene product 22,23 after systemic or tissue-specific administration of the high-dose viral vector needed to achieve therapeutic benefits.…”

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confidence: 99%