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Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy
Alessandro Aiuti, … , Fulvio Mavilio, Claudio Bordignon
Alessandro Aiuti, … , Fulvio Mavilio, Claudio Bordignon
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2233-2240. https://doi.org/10.1172/JCI31666.
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Research Article

Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy

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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.

Authors

Alessandro Aiuti, Barbara Cassani, Grazia Andolfi, Massimiliano Mirolo, Luca Biasco, Alessandra Recchia, Fabrizia Urbinati, Cristina Valacca, Samantha Scaramuzza, Memet Aker, Shimon Slavin, Matteo Cazzola, Daniela Sartori, Alessandro Ambrosi, Clelia Di Serio, Maria Grazia Roncarolo, Fulvio Mavilio, Claudio Bordignon

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Figure 1

RISs favor TSSs and gene-dense regions.

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RISs favor TSSs and gene-dense regions.
(A) Distribution of RISs within ...
(A) Distribution of RISs within a 30-kb window around TSSs. Each bar corresponds to the frequency of integration sites retrieved by LM-PCR technique in pretransplant CD34+ cells (in vitro, n = 212) or posttransplant hematopoietic cells (in vivo, n = 251) at 5-kb intervals from the TSS of the nearest gene. (B) Correlation between RISs and gene density in the human genome within a 1-Mb window. The number of RefSeq genes was determined in a region of 500 kb on either side of the RIS for both in vitro and in vivo samples. The data are compared with the average gene density of the human genome.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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