Nature Medicine
- 12, 585 - 591 (2006)
Published online: 23 April 2006; | doi:10.1038/nm1398
Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transferBrian D Brown1, Mary Anna Venneri1, Anna Zingale1, Lucia Sergi Sergi1 & Luigi Naldini1, 21
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), via Olgettina 58, 20132 Milano, Italy. 2
Vita Salute San Raffaele University, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy.
Correspondence should be addressed to Luigi Naldini naldini.luigi@hsr.it MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by repressing translation of target cellular transcripts. Increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in numerous cellular processes, although the extent of miRNA regulation is not well known. By challenging mice with lentiviral vectors encoding target sequences of endogenous miRNAs, we show the efficiency of miRNAs in sharply segregating gene expression among different tissues. Transgene expression from vectors incorporating target sequences for mir-142-3p was effectively suppressed in intravascular and extravascular hematopoietic lineages, whereas expression was maintained in nonhematopoietic cells. This expression profile, which could not be attained until now, enabled stable gene transfer in immunocompetent mice, thus overcoming a major hurdle to successful gene therapy. Our results provide novel in situ evidence of miRNA regulation and demonstrate a new paradigm in vector design with applications for genetic engineering and therapeutic gene transfer.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
