Researchers at St. Jude have discovered an inducibly activatable fusion protein composed of the Receptor Interacting Protein Kinase 3 (RIPK3) linked to 2 FKBP fragments (FV domains) that may act as a suicide switch for gene or cell therapy. The FV domains specifically bind a modified version of the drug rapamycin, which causes the RIPK3 to dimerize or oligomerize; with oligomerization of RIPK3 triggering cell death.
This construct may be useful in gene therapy or transferred tumor immunity where expression constructs or engineered cells are introduced into patients. Including protein elements as a potent “kill switch” could allow clinicians to specifically eliminate these cells in the event of adverse reactions or uncontrolled growth. It can also eliminate upstream activators of RIPK3, allowing direct assessment of downstream effectors using techniques such as siRNA screening, chemical screening, and phosphoproteomics. Lastly, specific induction of RIPK3-dependent necrosis may allow modulation of the immune response in tumor vaccines.
Cell Therapy, RIPK3, cancer, immunomodulation, suicide gene
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Related Scientific References
Tait SW, Oberst A, Quarato G, Milasta S, Haller M, Wang R, Karvela M, Ichim G, Yatim N, Albert ML, Kidd G, Wakefield R, Frase S, Krautwald S, Linkermann A, Green DR. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 2013 Nov 27;5(4):878-85. doi: 10.1016/j.celrep.2013.10.034. Epub 2013 Nov 21;
See also: YS Cho et al Cell 2009, S He et al Cell 2009; A. Oberst et al Nature 2011.
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Last update: March 2014