An inducible caspase 9 suicide gene to improve the safety of mesenchymal stromal cell therapies.
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.
Ramos
Carlos Almeida
CA
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA. caramos@bcm.edu
Asgari
Zahra
Z
Liu
Enli
E
Yvon
Eric
E
Heslop
Helen E
HE
Rooney
Clio M
CM
Brenner
Malcolm K
MK
Dotti
Gianpietro
G
D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D041722:Genes, Transgenic, Suicide; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID
D018941:Antigens, CD19; D015415:Biomarkers; D053453:Caspase 9