An Inducible Caspase 9 Suicide Gene to Improve the Safety of Mesenchymal Stromal Cell Therapies§

Authors

  • Carlos Almeida Ramos,

    Corresponding author
    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
    2. Departments of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    • Assistant Professor of Medicine, Center for Cell and Gene Therapy, Department of Medicine, Baylor College of Medicine, One Baylor Plaza BCM 505, Houston, Texas 77030, USA
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    • Telephone: 832-824-4817; Fax: 832-825-4732

  • Zahra Asgari,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
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  • Enli Liu,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
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  • Eric Yvon,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
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  • Helen E. Heslop,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
    2. Departments of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    3. Pediatrics, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
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  • Clio M. Rooney,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
    2. Pediatrics, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    3. Pathology and Immunology, andBaylor College of Medicine, Houston, Texas, USA
    4. Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
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  • Malcolm K. Brenner,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
    2. Departments of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
    3. Pediatrics, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
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  • Gianpietro Dotti

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA
    2. Departments of Medicine, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
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  • C.A.R.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; Z.A.: collection and/or assembly of data; E.L.: collection and/or assembly of data; E.Y.: provision of study material; H.E.H.: conception and design; C.M.R.: conception and design; M.K.B.: conception and design, manuscript writing; G.D.: conception and design, provision of study material, manuscript writing.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS April 28, 2010.

Abstract

Mesenchymal stromal cells (MSCs) have been infused in hundreds of patients to date, with minimal reported side effects. However, follow-up is limited and long-term side effects are unknown. Because several animal models have raised safety concerns, we sought to develop a system allowing control over the growth and survival of MSCs used therapeutically. We have previously described a suicide system based on an inducible caspase-9 (iCasp9) protein that is activated using a specific chemical inducer of dimerization (CID), analogs of which have been safely tested in a phase I study. Here, we show that MSCs can be easily transduced with this system and selected to high purity (greater than 97%) with clinical grade immunomagnetic procedures. The transduced cells maintain their basic physiology, including expression of surface antigens (such as positivity for CD73, CD90, and CD105, and negativity for hematopoietic markers) and their potential to differentiate into diverse connective tissue lineages (adipocytes, osteoblasts, and chondroblasts). Those cells and their differentiated progeny can be selectively eliminated in vitro or in vivo within 24 hours after exposure to pharmacological levels of CID, with evidence of apoptosis in more than 95% of iCasp9-positive cells. In conclusion, we have developed directed MSC killing to provide a necessary safety mechanism for therapies using progenitor cells. We believe that this approach will become of increasing value as clinical applications for MSCs develop further. STEM Cells 2010;28:1107–1115

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