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- Title
A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference.
- Authors
Samakoglu, Selda; Lisowski, Leszek; Budak-Alpdogan, Tulin; Usachenko, Yelena; Acuto, Santina; Di Marzo, Rosalba; Maggio, Aurelio; Zhu, Ping; Tisdale, John F.; Riviere, Isabelle; Sadelain, Michel
- Abstract
The application of RNA interference (RNAi) to stem cell–based 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 βS transcripts, thus providing proof of principle for therapeutic strategies that require synergistic gene addition and gene silencing in stem cell progeny.
- Subjects
SICKLE cell anemia treatment; TRANSGENE expression; GENE silencing; GENETIC regulation; GENE therapy
- Publication
Nature Biotechnology, 2006, Vol 24, Issue 1, p89
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt1176