Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer

Brian D. Brown, Mary Anna Venneri, Anna Zingale, Lucia Sergi Sergi, Luigi Naldini

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)585-591
Number of pages7
JournalNature Medicine
Volume12
Issue number5
DOIs
Publication statusPublished - May 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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