Prolonged survival and phenotypic correction of Akp2−/− hypophosphatasia mice by lentiviral gene therapy

Yamamoto, Setsu; Orimo, Hideo; Matsumoto, Tae; Iijima, Osamu; Narisawa, Sonoko; Maeda, Takeyasu; Millán, José Luis; Shimada, Takashi

doi:10.1002/jbmr.201

Cited by 55 publications

(53 citation statements)

References 38 publications

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“…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%

“…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: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia

et al. 2012

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“…Similarly, TNAP knockout mice (Akp2−/−) accumulate extracellular PP i , reveal hypomineralization [488][489][490][491], and can serve as a model for the infantile form of hypophosphatasia [492]. The defect can be eliminated by subcutaneous injections of soluble TNAP targeted to mineralizing tissue [493,494] or by lentiviral application of a bone-targeted form of TNAP [495].…”

Section: Substrates and Catalytic Propertiesmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

872

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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“…Recently, many studies have been conducted using the HPP mouse model (Alpl -/-) to clarify the mechanisms underlying the abnormal calcification in hard tissue accompanying Alpl gene mutations (6,7). Several reports contained histological examination of the dentin and cementum defects in Alpl -/-mice (8)(9)(10).…”

Section: Oral Manifestations Of Hpp Include a Characteristicmentioning

confidence: 99%

Enamel Defects in the Alpl- /- murine Model of Infantile Hypophosphatasia

Yokoi

Yamamoto-Nemoto

2017

Int J Oral-Med Sci

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Hypophosphatasia(HPP)is caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL). HPP patients develop deficient calcification of bones and teeth including defects in cementum, dentin, and enamel and the characteristic premature loss of primary teeth. Here, we investigated the enamel defects of knockout(Alpl -/-)mice compared with that of control wild type(Alpl +/+ )mice.No alkaline phosphatase (ALP) activity was detected by specific staining in the first molar germ of Alpl -/-mice on postnatal day 5. Hematoxylin and eosin staining revealed that the enamel layer in Alpl -/-mice was thin, undulated, and rugged. Furthermore, Alpl Our study suggests that ALP may have involvement in EMPs and enamel defects in Alpl -/-mice is caused by ameloblasts disorder. Furthermore, our study advances elucidation of the mechanisms that underlie enamel development, and will support establish the causes of enamel defects of HPP patients.

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Prolonged survival and phenotypic correction of Akp2−/− hypophosphatasia mice by lentiviral gene therapy

Cited by 55 publications

References 38 publications

Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia

Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia

Cellular function and molecular structure of ecto-nucleotidases

<b>Enamel Defects in the </b><b><i>Alpl</i></b><b><sup>- /- </sup></b><b>murine Model of Infantile Hypophosphatasia </b>

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