Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy.
J Clin Invest
; 117(8): 2233-40, 2007 Aug.
Article
em En
| MEDLINE
| ID: mdl-17671653
ABSTRACT
Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis. We performed a genome-wide analysis of retroviral vector integrations in genetically corrected HSCs and their multilineage progeny before and up to 47 months after transplantation into 5 patients with adenosine deaminase-deficient SCID. Gene-dense regions, promoters, and transcriptionally active genes were preferred retroviral integrations sites (RISs) both in preinfusion transduced CD34(+) cells and in vivo after gene therapy. The occurrence of insertion sites proximal to protooncogenes or genes controlling cell growth and self renewal, including LMO2, was not associated with clonal selection or expansion in vivo. Clonal analysis of long-term repopulating cell progeny in vivo revealed highly polyclonal T cell populations and shared RISs among multiple lineages, demonstrating the engraftment of multipotent HSCs. These data have important implications for the biology of retroviral vectors, the dynamics of genetically modified HSCs, and the safety of gene therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Retroviridae
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Terapia Genética
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Adenosina Desaminase
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Mutagênese Insercional
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Integração Viral
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Imunodeficiência Combinada Severa
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Transplante de Células-Tronco Hematopoéticas
Tipo de estudo:
Clinical_trials
/
Etiology_studies
/
Risk_factors_studies
Limite:
Child, preschool
/
Female
/
Humans
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Infant
/
Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Itália