Format

Send to

Choose Destination
Nat Biotechnol. 2007 Dec;25(12):1457-67. Epub 2007 Nov 16.

Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state.

Author information

1
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, via Olgettina, 58, 20132 Milan, Italy.

Abstract

We have shown previously that transgene expression can be suppressed in hematopoietic cells using vectors that are responsive to microRNA (miRNA) regulation. Here we investigate the potential of this approach for more sophisticated control of transgene expression. Analysis of the relationship between miRNA expression levels and target mRNA suppression suggested that suppression depends on a threshold miRNA concentration. Using this information, we generated vectors that rapidly adjust transgene expression in response to changes in miRNA expression. These vectors sharply segregated transgene expression between closely related states of therapeutically relevant cells, including dendritic cells, hematopoietic and embryonic stem cells, and their progeny, allowing positive/negative selection according to the cells' differentiation state. Moreover, two miRNA target sites were combined to restrict transgene expression to a specific cell type in the liver. Notably, the vectors did not detectably perturb endogenous miRNA expression or regulation of natural targets. The properties of miRNA-regulated vectors should allow for safer and more effective therapeutic applications.

PMID:
18026085
DOI:
10.1038/nbt1372
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center