論文

査読有り
2015年12月

Prevention of Lethal Murine Hypophosphatasia by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells

HUMAN GENE THERAPY
  • Osamu Iijima
  • ,
  • Koichi Miyake
  • ,
  • Atsushi Watanabe
  • ,
  • Noriko Miyake
  • ,
  • Tsutomu Igarashi
  • ,
  • Chizu Kanokoda
  • ,
  • Aki Nakamura-Takahashi
  • ,
  • Hideaki Kinoshita
  • ,
  • Taku Noguchi
  • ,
  • Shinichi Abe
  • ,
  • Sonoko Narisawa
  • ,
  • Jose Luis Millan
  • ,
  • Takashi Okada
  • ,
  • Takashi Shimada

26
12
開始ページ
801
終了ページ
812
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1089/hum.2015.078
出版者・発行元
MARY ANN LIEBERT, INC

Hypophosphatasia (HPP) is an inherited skeletal and dental disease caused by loss-of-function mutations in the gene that encodes tissue-nonspecific alkaline phosphatase (TNALP). The major symptoms of severe forms of the disease are bone defects, respiratory insufficiency, and epileptic seizures. In 2015, enzyme replacement therapy (ERT) using recombinant bone-targeted TNALP with deca-aspartate (D-10) motif was approved to treat pediatric HPP patients in Japan, Canada, and Europe. However, the ERT requires repeated subcutaneous administration of the enzyme because of the short half-life in serum. In the present study, we evaluated the feasibility of neonatal ex vivo gene therapy in TNALP knockout (Akp2(-/-)) HPP mice using lentivirally transduced bone marrow cells (BMC) expressing bone-targeted TNALP in which a D-10 sequence was linked to the C-terminus of soluble TNALP (TNALP-D-10). The Akp2(-/-) mice usually die within 20 days because of growth failure, epileptic seizures, and hypomineralization. However, an intravenous transplantation of BMC expressing TNALP-D-10 (ALP-BMC) into neonatal Akp2(-/-) mice prolonged survival of the mice with improved bone mineralization compared with untransduced BMC-transplanted Akp2(-/-) mice. The treated Akp2(-/-) mice were normal in appearance and experienced no seizures during the experimental period. The lentivirally transduced BMC were efficiently engrafted in the recipient mice and supplied TNALP-D-10 continuously at a therapeutic level for at least 3 months. Moreover, TNALP-D-10 overexpression did not affect multilineage reconstitution in the recipient mice. The plasma ALP activity was sustained at high levels in the treated mice, and tissue ALP activity was selectively detected on bone surfaces, not in the kidneys or other organs. No ectopic calcification was observed in the ALP-BMC-treated mice. These results indicate that lentivirally transduced BMC can serve as a reservoir for stem cell-based ERT to rescue the Akp2(-/-) phenotype. Neonatal ex vivo gene therapy thus appears to be a possible treatment option for treating severe HPP.

Web of Science ® 被引用回数 : 12

リンク情報
DOI
https://doi.org/10.1089/hum.2015.078
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26467745
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000366833500005&DestApp=WOS_CPL

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