A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference Journal Article


Authors: Samakoglu, S.; Lisowski, L.; Budak-Alpdogan, T.; Usachenko, Y.; Acuto, S.; Di Marzo, R.; Maggio, A.; Zhu, P.; Tisdale, J. F.; Riviere, I.; Sadelain, M.
Article Title: A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference
Abstract: The application of RNA interference (RNAi) to stem cell-based gene therapies will require highly specific and lineage-restricted gene silencing. Here we show the feasibility and therapeutic potential of coregulating transgene expression and RNAi in hematopoietic stem cells. We encoded promoterless small-hairpin RNA (shRNA) within the intron of a recombinant γ-globin gene. Expression of both γ-globin and the lariat-embedded small interfering RNA (siRNA) was induced upon erythroid differentiation, specifically downregulating the targeted gene in tissue- and differentiation stage-specific fashion. The position of the shRNA within the intron was critical to concurrently achieve high-level transgene expression, effective siRNA generation and minimal interferon induction. Lentiviral transduction of CD34 + cells from patients with sickle cell anemia led to erythroid-specific expression of the γ-globin transgene and concomitant reduction of endogenous β S transcripts, thus providing proof of principle for therapeutic strategies that require synergistic gene addition and gene silencing in stem cell progeny. © 2006 Nature Publishing Group.
Keywords: controlled study; treatment outcome; human cell; promoter region; interferon; cells, cultured; gene targeting; cd34 antigen; gene expression; small interfering rna; intron; rna interference; cell differentiation; gene transfer; viral gene delivery system; genetic transduction; rna; gene expression regulation; feasibility study; genetic engineering; cell culture; recombinant protein; gene therapy; lentivirus; lentivirus vector; erythroid cell; transgene; hematopoietic stem cells; protein induction; down regulation; hematopoietic stem cell; gene silencing; patient treatment; short hairpin rna; tissue; globins; cells; sickle cell anemia; gamma globin; anemia, sickle cell; genetic strategy; cell based gene therapy; cell progeny; stem cell-based gene therapies; recombinant gene
Journal Title: Nature Biotechnology
Volume: 24
Issue: 1
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2006-01-01
Start Page: 89
End Page: 94
Language: English
DOI: 10.1038/nbt1176
PUBMED: 16378095
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 56" - "Export Date: 4 June 2012" - "CODEN: NABIF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Michel W J Sadelain
    462 Sadelain
  2. Isabelle C Riviere
    168 Riviere
  3. Ping Zhu
    2 Zhu