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Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy.
J Clin Invest ; 117(8): 2225-32, 2007 Aug.
Article en En | MEDLINE | ID: mdl-17671652
ABSTRACT
Recent reports have challenged the notion that retroviruses and retroviral vectors integrate randomly into the host genome. These reports pointed to a strong bias toward integration in and near gene coding regions and, for gammaretroviral vectors, around transcription start sites. Here, we report the results obtained from a large-scale mapping of 572 retroviral integration sites (RISs) isolated from cells of 9 patients with X-linked SCID (SCID-X1) treated with a retrovirus-based gene therapy protocol. Our data showed that two-thirds of insertions occurred in or very near to genes, of which more than half were highly expressed in CD34(+) progenitor cells. Strikingly, one-fourth of all integrations were clustered as common integration sites (CISs). The highly significant incidence of CISs in circulating T cells and the nature of their locations indicate that insertion in many gene loci has an influence on cell engraftment, survival, and proliferation. Beyond the observed cases of insertional mutagenesis in 3 patients, these data help to elucidate the relationship between vector insertion and long-term in vivo selection of transduced cells in human patients with SCID-X1.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Terapia Genética / Genoma Humano / Integración Viral / Gammaretrovirus / Linfopoyesis / Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X / Vectores Genéticos Tipo de estudio: Guideline Límite: Humans Idioma: En Año: 2007 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Terapia Genética / Genoma Humano / Integración Viral / Gammaretrovirus / Linfopoyesis / Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X / Vectores Genéticos Tipo de estudio: Guideline Límite: Humans Idioma: En Año: 2007 Tipo del documento: Article