Thymidine kinase suicide gene-mediated ganciclovir ablation of autologous gene-modified rhesus hematopoiesis.
Mol Ther
; 20(10): 1932-43, 2012 Oct.
Article
in En
| MEDLINE
| ID: mdl-22910293
ABSTRACT
Despite the genotoxic complications encountered in clinical gene therapy trials for primary immunodeficiency diseases targeting hematopoietic cells with integrating vectors; this strategy holds promise for the cure of several monogenic blood, metabolic and neurodegenerative diseases. In this study, we asked whether the inclusion of a suicide gene in a standard retrovirus vector would allow elimination of vector-containing stem and progenitor cells and their progeny in vivo following transplantation, using our rhesus macaque transplantation model. Following stable engraftment with autologous CD34(+) cells transduced with a retrovirus vector encoding a highly sensitive modified Herpes simplex virus thymidine kinase SR39, the administration of the antiviral prodrug ganciclovir (GCV) was effective in completely eliminating vector-containing cells in all hematopoietic lineages in vivo. The sustained absence of vector-containing cells over time, without additional GCV administration, suggests that the ablation of TkSR39 GCV-sensitive cells occurred in the most primitive hematopoietic long-term repopulating stem or progenitor cell compartment. These results are a proof-of-concept that the inclusion of a suicide gene in integrating vectors, in addition to a therapeutic gene, can provide a mechanism for later elimination of vector-containing cells, thereby increasing the safety of gene transfer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thymidine Kinase
/
Ganciclovir
/
Genes, Transgenic, Suicide
/
Genetic Vectors
/
Hematopoiesis
Limits:
Animals
Language:
En
Journal:
Mol Ther
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2012
Document type:
Article
Affiliation country:
Estados Unidos