Development of a Safeguard System Using an Episomal Mammalian Artificial Chromosome for Gene and Cell Therapy

Molecular Therapy: Nucleic Acids

Narumi Uno¹  Yasuhiro Kazuki¹  Mitsuo Oshimura¹  Shinya Komoto²  Katsuhiro Uno²  Masaharu Hiratsuka³  Mitsuhiko Osaki⁴  Teruhiko Suzuki⁵ 

[1] Chromosome Engineering Research Center, Tottori University, Yonago, Japan;Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan;Department of Molecular and Cellular Biology, Faculty of Medicine, Tottori University, Yonago, Japan;Division of Pathological Biochemistry, Faculty of Medicine, Tottori University, Yonago, Japan;Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;

关键词: cancer immunotherapy;    gene and cell therapy;    HAC;    MAC;    major histocompatibility complex;    mammalian artificial chromosome;    pluripotent stem cell;    regenerative medicine;    safeguard system;    tumor suppression;   

DOI  :  10.1038/mtna.2015.45

来源: DOAJ

【 摘 要 】

The development of a safeguard system to remove tumorigenic cells would allow safer clinical applications of stem cells for the treatment of patients with an intractable disease including genetic disorders. Such safeguard systems should not disrupt the host genome and should have long-term stability. Here, we attempted to develop a tumor-suppressing mammalian artificial chromosome containing a safeguard system that uses the immune rejection system against allogeneic tissue from the host. For proof-of-concept of the safeguard system, B16F10 mouse melanoma cells expressing the introduced H2-K(d) major histocompatibility complex (MHC class I)-allogenic haplotype were transplanted into recipient C57BL/6J mice expressing MHC H2-K(b). Subcutaneous implantation of B16F10 cells into C57BL/6J mice resulted in high tumorigenicity. The volume of tumors derived from B16F10 cells expressing allogenic MHC H2-K(d) was decreased significantly (P < 0.01). Suppression of MHC H2-K(d)-expressing tumors in C57BL/6J mice was enhanced by immunization with MHC H2-K(d)-expressing splenocytes (P < 0.01). These results suggest that the safeguard system is capable of suppressing tumor formation by the transplanted cells.

【 授权许可】

Unknown