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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3138-3147.
Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2008-03-142661.

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GENE THERAPY

Unaltered repopulation properties of mouse hematopoietic stem cells transduced with lentiviral vectors

Africa Gonzalez-Murillo1, M. Luz Lozano1, Eugenio Montini2, Juan A. Bueren1, and Guillermo Guenechea1

1 Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Eufermedades Raras (CIBERER), Madrid, Spain; and 2 Ospedale San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET), Milano, Italy

Recent studies of retroviral-mediated gene transfer have shown that retroviral integrations themselves may trigger nonmalignant clonal expansion of hematopoietic stem cells (HSCs) in transplant recipients. These observations suggested that previous conclusions of HSC dynamics based on gamma-retroviral gene marking should be confirmed with improved vectors having a more limited capacity to transactivate endogenous genes. Because of the low trans-activation activity of self-inactivating lentiviral vectors (LVs), we have investigated whether the LV marking of mouse HSCs induces a competitive repopulation advantage in recipients of serially transplants. As deduced from analyses conducted in primary and secondary recipients, we concluded that lentivirally transduced HSCs have no competitive repopulation advantages over untransduced HSCs. By linear amplification-mediated polymerase chain reaction (LAM-PCR) analysis, we characterized LV-targeted genes in HSC clones that engrafted up to quaternary recipients. Although 9 clones harbored integrations close to defined retroviral insertion sites, none was characterized as a common integration site, and none was present in HSC clones repopulating quaternary recipients. Taken together, our results show unaltered repopulation properties of HSCs transduced with LVs, and confirm early studies suggesting the natural capacity of a few HSC clones to generate a monoclonal or oligoclonal hematopoiesis in transplant recipients.


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