Remarkably, SCID was the first condition to be corrected by gene therapy, just as it was the first ever indication for allogeneic HSC transplantation (HSCT Gatti et al., 1968). At the time of writing, regulatory authorities in Europe have approved one gene therapy product of primary immunodeficiency (PID), Strimvelis, to treat ADA SCID ( Aiuti et al., 2017). Gene therapy has thus become a reality, paving the way for the treatment of other diseases. The first attempts at correcting SCID caused by adenosine deaminase (ADA) deficiency, however, failed because the technology was not yet optimal ( Blaese et al., 1995 Kohn et al., 1995 Hoogerbrugge et al., 1996).Īdvances in HSC biology, the identification of genes associated with SCID, a better understanding of SCID pathophysiology, and empirical improvements in cell transduction protocols led to the first effective treatments. The development of ad hoc vector packaging cell lines resulted in replication-incompetent vectors ( Miller and Buttimore, 1986 Danos and Mulligan, 1988). Murine retroviruses were the first to be used to transduce hematopoietic stem cells (HSCs Williams et al., 1984). Once the biology of retroviruses was characterized ( Varmus, 1988 Temin and Mizutani, 1970), it became clear that they could be used as vectors for integrating a transgene into targeted cells and enabling expression. Nevertheless, it took almost 30 yr and several key advances to become a reality. The concept of gene therapy emerged >50 yr ago ( Friedmann and Roblin, 1972) at a time when (i) the basic principles of molecular biology had been determined and (ii) the first disease-causing genetic mutations were being discovered. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott–Aldrich syndrome, while further applications are pending. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy.
Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency.
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