A highly stable and nonintegrated human artificial chromosome (HAC) containing the 2.4 Mb entire human dystrophin gene

Hidetoshi Hoshiya, Yasuhiro Kazuki, Satoshi Abe, Masato Takiguchi, Naoyo Kajitani, Yoshinori Watanabe, Toko Yoshino, Yasuaki Shirayoshi, Katsumi Higaki, Graziella Messina, Giulio Cossu, Mitsuo Oshimura

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Episomal vector with the capacity to deliver a large gene containing all the critical regulatory elements is ideal for gene therapy. Human artificial chromosomes (HACs) have the capacity to deliver an extremely large genetic region to host cells without integration into the host genome, thus preventing possible insertional mutagenesis and genomic instability. Duchenne muscular dystrophy (DMD) is caused by mutation in the extremely large dystrophin gene (2.4 Mb). We herein report the development of a HAC vector containing the entire human dystrophin gene (DYS-HAC) that is stably maintained in mice and human immortalized mesenchymal stem cells (hiMSCs). The DYS-HAC was transferred to mouse embryonic stem (ES) cells, and isoforms of the DYS-HAC-derived human dystrophin in the chimeric mice generated from the ES cells were correctly expressed in tissue-specific manner. Thus, this HAC vector containing the entire dystrophin gene with its native regulatory elements is expected to be extremely useful for future gene and cell therapies of DMD.
    Original languageEnglish
    Pages (from-to)309-317
    Number of pages8
    JournalMolecular Therapy
    Volume17
    Issue number2
    DOIs
    Publication statusPublished - 2009

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