Correction of murine ß-thalassemia after minimal lentiviral gene transfer and homeostatic in vivo erythroid expansion.
Blood
; 117(20): 5321-31, 2011 May 19.
Article
in En
| MEDLINE
| ID: mdl-21436071
ABSTRACT
A challenge for gene therapy of genetic diseases is to maintain corrected cell populations in subjects undergoing transplantation in cases in which the corrected cells do not have intrinsic selective advantage over nontransduced cells. For inherited hematopoietic disorders, limitations include inefficient transduction of stem cell pools, the requirement for toxic myelosuppression, and a lack of optimal methods for cell selection after transduction. Here, we have designed a lentiviral vector that encodes human ß-globin and a truncated erythropoietin receptor, both under erythroid-specific transcriptional control. This truncated receptor confers enhanced sensitivity to erythropoietin and a benign course in human carriers. Transplantation of marrow transduced with the vector into syngenic thalassemic mice, which have elevated plasma erythropoietin levels, resulted in long-term correction of the disease even at low ratios of transduced/untransduced cells. Amplification of the red over the white blood cell lineages was self-controlled and averaged â¼ 100-fold instead of â¼ 5-fold for ß-globin expression alone. There was no detectable amplification of white blood cells or alteration of hematopoietic homeostasis. Notwithstanding legitimate safety concerns in the context of randomly integrating vectors, this approach may prove especially valuable in combination with targeted integration or in situ homologous recombination/repair and may lower the required level of pretransplantation myelosuppression.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Therapy
/
Beta-Thalassemia
Limits:
Animals
/
Humans
Language:
En
Journal:
Blood
Year:
2011
Type:
Article
Affiliation country:
France