Clonal evidence for the transduction of CD34+ cells with lymphomyeloid differentiation potential and self-renewal capacity in the SCID-X1 gene therapy trial.

Abstract:

:Immune function has been restored in 9 of 10 children with X-linked severe combined immunodeficiency by gamma c gene transfer in CD34+ cells. The distribution of both T-cell receptor (TCR) V beta family usage and TCR V beta 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 gamma 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.

journal_name

Blood

journal_title

Blood

authors

Schmidt M,Hacein-Bey-Abina S,Wissler M,Carlier F,Lim A,Prinz C,Glimm H,Andre-Schmutz I,Hue C,Garrigue A,Le Deist F,Lagresle C,Fischer A,Cavazzana-Calvo M,von Kalle C

doi

10.1182/blood-2004-07-2648

subject

Has Abstract

pub_date

2005-04-01 00:00:00

pages

2699-706

issue

7

eissn

0006-4971

issn

1528-0020

pii

2004-07-2648

journal_volume

105

pub_type

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