Linking a cell-division gene and a suicide gene to define and improve cell therapy safety.

Autor: Liang Q; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Monetti C; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada., Shutova MV; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada., Neely EJ; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Hacibekiroglu S; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Yang H; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Kim C; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Zhang P; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada., Li C; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada., Nagy K; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; Department of Physiology, University of Toronto, Toronto, Ontario, Canada., Mileikovsky M; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada., Gyongy I; School of Mathematics and Maxwell Institute, The University of Edinburgh, Edinburgh, UK., Sung HK; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.; The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada., Nagy A; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. nagy@lunenfeld.ca.; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. nagy@lunenfeld.ca.; Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia. nagy@lunenfeld.ca.; Department of Obstetrics & Gynaecology, University of Toronto, Toronto, Ontario, Canada. nagy@lunenfeld.ca.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 Nov; Vol. 563 (7733), pp. 701-704. Date of Electronic Publication: 2018 Nov 14.
DOI: 10.1038/s41586-018-0733-7
Abstrakt: Human pluripotent cell lines hold enormous promise for the development of cell-based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes 1 , but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system. Furthermore, we used a mathematical model to quantify the safety level of the cell therapy as a function of the number of cells that is needed for the therapy and the type of genome editing that is performed. Even with the highly conservative estimates described here, we anticipate that our solution will rapidly accelerate the entry of cell-based medicine into the clinic.
Databáze: MEDLINE
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