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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2699-2706.
Prepublished online as a Blood First Edition Paper on December 7, 2004; DOI 10.1182/blood-2004-07-2648.
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GENE THERAPY
Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial
Manfred Schmidt,
Salima Hacein-Bey-Abina,
Manuela Wissler,
Frederique Carlier,
Annick Lim,
Claudia Prinz,
Hanno Glimm,
Isabelle Andre-Schmutz,
Christophe Hue,
Alexandrine Garrigue,
Francoise Le Deist,
Chantal Lagresle,
Alain Fischer,
Marina Cavazzana-Calvo, and
Christof von Kalle
From the Department of Internal Medicine, University of Freiburg, Germany; Institute of Molecular Medicine and Cell Research, University of Freiburg, Germany; Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 429, Hôpital Necker, Paris, France; Department of Biotherapy AP-HP, Hôpital Necker, Paris, France; Unité de Biologie Moléculaire du Gène, INSERM U277, Institut Pasteur, Paris, France; Laboratoire d'Immunologie Pédiatrique, AP-HP, Hôpital Necker, Paris, France; Unité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker, Paris, France; and Department of Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, OH.
Immune function has been restored in 9 of 10 children with X-linked severe combined immunodeficiency by  c gene transfer in CD34+ cells. The distribution of both T-cell receptor (TCR) V family usage and TCR V complementarity-determining region 3 (CDR3) length revealed a broadly diversified T-cell repertoire. Retroviral integration site analysis in T cells demonstrated a high number of distinct insertion sites, indicating polyclonality of genetically corrected cell clones, in all patients. Detection of c transgene expression on patients' mature myeloid cells has prompted us to investigate the nature of the most immature transduced hematopoietic precursor cells. Insertion sites shared by T and B lymphocytes as well as highly purified granulocytes and monocytes demonstrate the correction of common multipotent progenitor cells. Moreover, our data show that differentiated leukocytes share the same exact insertion sites with CD34+ cells that we obtained 8 months later and that were able to generate long-term culture-initiating cells (LTC-ICs). This finding demonstrates the initial transduction of very primitive multipotent progenitor cells with self-renewal capacity. These results provide a first evidence in the setting of a clinical trial that CD34+ cells maintain both lymphomyeloid potential as well as self-renewal capacity after ex vivo manipulation.
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