Michel Sadelain and colleagues, at Memorial Sloan-Kettering Cancer Center, New York, have developed a new approach to modulate the expression of genes for therapeutic purposes, and used this to mediate effective anticancer therapy in mice.
Small, noncoding RNA molecules known as miRNAs are powerful natural repressors of gene expression. In the study, the miRNA miR-181a was harnessed to segregate expression of genes in immune cells known as T cells at different stages of their development. miR-181a is highly expressed in developing T cells, in which it represses expression of many genes, and markedly downregulated in mature T cells. Sadelain and colleagues engineered mouse bone marrow cells to express therapeutic genes only when miR-181a expression is downregulated. These cells were then transplanted into mice and allowed to develop into mature T cells. Expression of the genes (and therefore the proteins made from the genes) was not detected in developing T cells, i.e., when miR-181a was highly expressed, but was detected in mature T cells, i.e., when miR-181a was downregulated. When the genes controlled by miR-181a were responsible for making proteins that target T cells to tumor cells expressing the protein hCD19, the mice that were transplanted with the engineered bone marrow cells were able to reject tumors expressing hCD19. The authors therefore suggest that it might be possible to harness miRNA-regulated therapeutic gene expression in stem cell-based therapies, including cancer immunotherapy.
TITLE: Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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