IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential

Francesca Ficara, Daniela B. Superchi, Raisa Jofra Hernández, Cristina Mocchetti, Nicole Carballido-Perrig, Grazia Andolfi, Sara Deola, Augusto Colombo, Claudio Bordignon, José M. Carballido, Maria Grazia Roncarolo, Alessandro Aiuti

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

To improve maintenance and gene transfer of human lymphoid progenitors for clinical use in gene therapy of adenosine deaminase (ADA)-deficient SCID we investigated several gene transfer protocols using various stem cell-enriched sources. The lymphoid differentiation potential was measured by an in vitro clonal assay for B/NK cells and in the in vivo SCID-hu mouse model. Ex vivo culture with the cytokines TPO, FLT3-ligand, and SCF (T/F/S) plus IL-3 or IL-7 substantially increased the yield of transduced bone marrow (BM) CD34+ cells purified from ADA-SCID patients or healthy donors, compared to T/F/S alone. Moreover, the use of IL-3 or IL-7 significantly improved the maintenance of in vitro B cell progenitors from ADA-SCID BM cells and allowed the efficient transduction of B and NK cell progenitors. Under these optimized conditions transduced CD34+ cells were efficiently engrafted into SCID-hu mice and gave rise to B and T cell progeny, demonstrating the maintenance of in vivo lymphoid reconstitution capacity. The protocol based on the T/F/S + IL-3 combination was included in a gene therapy clinical trial for ADA-SCID, resulting in long-term engraftment of stem/progenitor cells. Remarkably, gene-corrected BM CD34+ cells obtained from one patient 4 and 11 months after gene therapy were capable of repopulating the lymphoid compartment of SCID-hu hosts.

Original languageEnglish
Pages (from-to)1096-1108
Number of pages13
JournalMolecular Therapy
Volume10
Issue number6
DOIs
Publication statusPublished - 1 Dec 2004
Externally publishedYes

Fingerprint

Interleukin-7
Adenosine Deaminase
Interleukin-3
Bone Marrow Cells
Genetic Therapy
Stem Cells
SCID Mice
Maintenance
Ligands
Natural Killer Cells
Genes
B-Lymphocytes
B-Lymphoid Precursor Cells
Tissue Donors
Clinical Trials
Cytokines
T-Lymphocytes
In Vitro Techniques

Keywords

  • ADA-SCID
  • Human stem/progenitor cells
  • Immunodeficiency
  • Lymphoid differentiation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Ficara, F., Superchi, D. B., Hernández, R. J., Mocchetti, C., Carballido-Perrig, N., Andolfi, G., ... Aiuti, A. (2004). IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential. Molecular Therapy, 10(6), 1096-1108. https://doi.org/10.1016/j.ymthe.2004.08.014

IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential. / Ficara, Francesca; Superchi, Daniela B.; Hernández, Raisa Jofra; Mocchetti, Cristina; Carballido-Perrig, Nicole; Andolfi, Grazia; Deola, Sara; Colombo, Augusto; Bordignon, Claudio; Carballido, José M.; Roncarolo, Maria Grazia; Aiuti, Alessandro.

In: Molecular Therapy, Vol. 10, No. 6, 01.12.2004, p. 1096-1108.

Research output: Contribution to journalArticle

Ficara, F, Superchi, DB, Hernández, RJ, Mocchetti, C, Carballido-Perrig, N, Andolfi, G, Deola, S, Colombo, A, Bordignon, C, Carballido, JM, Roncarolo, MG & Aiuti, A 2004, 'IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential', Molecular Therapy, vol. 10, no. 6, pp. 1096-1108. https://doi.org/10.1016/j.ymthe.2004.08.014
Ficara, Francesca ; Superchi, Daniela B. ; Hernández, Raisa Jofra ; Mocchetti, Cristina ; Carballido-Perrig, Nicole ; Andolfi, Grazia ; Deola, Sara ; Colombo, Augusto ; Bordignon, Claudio ; Carballido, José M. ; Roncarolo, Maria Grazia ; Aiuti, Alessandro. / IL-3 or IL-7 increases ex vivo gene transfer efficiency in ADA-SCID BM CD34+ cells while maintaining in vivo lymphoid potential. In: Molecular Therapy. 2004 ; Vol. 10, No. 6. pp. 1096-1108.
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