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Identification of the molecular basis of the disease and development of more effective strategies of gene transfer into hematopoietic stem cells (HSCs) have opened the way to innovative forms of gene therapy for primary immunodeficiency (PID). In these approaches, a normal copy of the gene of interest is introduced into the genome of autologous HSCs that are then re-infused into the patient. Gene therapy also holds the potential for gene editing, which is actually the removal and correction of an aberration in an individual PID-causing gene. In this chapter, we will review the current status of gene therapy (including gene editing) for PIDs and discuss possible developments in the field.


Despite improved outcomes of hematopoietic cell transplantations (HCTs) for PID, treatment-related morbidity and mortality (in particular those caused by drug toxicity, graft rejection/graft failure, graft-versus-host disease [GVHD], and incomplete immune reconstitution and immune dysregulation) remain major problems. Furthermore, HCT from human leukocyte antigen (HLA)-matched related donors is available to only approximately 15% of patients with PID, and suitable unrelated donors are not available for a significant number of patients. The identification of the genetic bases of PIDs has opened the perspective of novel therapeutic approaches based on gene therapy. With this strategy, a normal copy of the disease-related gene is delivered to the patient’s own HSCs and is stably integrated in the genomic DNA, so that at each cell division, it is maintained into the genome of progeny cells (Fig. 186-1). As compared to HCT, gene therapy has the advantage that it should avoid the immunologic complications of allogeneic HSCT (graft rejection and GVHD in particular). However, current approaches of gene therapy also have important limitations. In particular, integration of the transgene into the host genome happens randomly or quasi-randomly; if the integration occurs within or near an oncogene, there is a potential for oncogene transactivation and tumor development. Furthermore, in most cases, expression of the therapeutic transgene is controlled by heterologous regulatory elements (promoters), potentially leading to dysregulated expression of the gene. These promises, but also these risks, have been confirmed in clinical trials.

Figure 186-1

Schematic representation of gene therapy. CD34+ hematopoietic stem cells (HSCs) are collected and isolated from bone marrow or upon mobilization into peripheral blood and are then subjected to in vitro transduction with viral vectors containing the therapeutic gene of interest (indicated in red). This allows stable integration of the transgene into the DNA of the CD34+ HSCs, which are then re-infused into the patient. Chemotherapy may be used to displace the endogenous, uncorrected HSCs, and facilitate long-term engraftment of gene-modified HSCs.


Because of the strong selective advantage for genetically intact progenitor cells to differentiate into T lymphocytes (even with no or little conditioning), severe combined immunodeficiency (SCID) ...

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