Preclinical protocol for in vivo selection of hematopoietic stem cells corrected by gene therapy in Fanconi anemia group C.
Mol Ther
; 3(1): 14-23, 2001 Jan.
Article
em En
| MEDLINE
| ID: mdl-11162306
ABSTRACT
Fanconi anemia (FA) is an autosomal recessive disorder characterized by birth defects, increased incidence of malignancy, progressive bone marrow failure, and cellular hypersensitivity to DNA cross-linking agents. Bone marrow transplantation is therapeutic and therefore FA is a candidate disease for hematopoietic gene therapy. We have previously used mitomycin C (MMC) to achieve in vivo selection of wild-type hematopoietic stem cells (HSC) transplanted into FANCC knockout mice. However, clinical application of MMC in human FA gene therapy is unlikely because of its unknown toxicity profile in human FA patients. In contrast, cyclophosphamide (CPA) and gamma-irradiation (IR) are already in use with human FA patients and we therefore tested these regimens for their ability to achieve selection of genetically corrected HSCs in vivo. We found that nonmyeloablative doses of CPA or IR or combinations of CPA + IR were highly efficient at achieving in vivo selection of transplanted wild-type HSC. Furthermore, this nontoxic regimen also selected FANCC-mutant HSC corrected by ex vivo retroviral gene therapy. We suggest those nontoxic doses of CPA and/or IR could also be used to enhance gene therapy in human FA patients.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
/
Terapia Genética
/
Anemia de Fanconi
Tipo de estudo:
Guideline
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Mol Ther
Assunto da revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Estados Unidos