Gene therapy for severe combined immunodeficiencies and beyond

Abstract

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. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural 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. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. 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. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.

Figure 1.

Spontaneous partial correction of SCID-X1 by reversion of the IL2RG mutation in a T cell precursor. The revertant cell (IL2RG wild type) was able to proliferate extensively before the TCRB variable diversity joining segments recombination stage. It generates a rather diverse repertoire, since 1,000 distinct TCRB sequences were expressed by mature CD4 and CD8 T cells. These cells expanded too, since the patient’s T cell count was approximately half that of age-matched controls (Stephan et al., 1996; Revy et al., 2019). A similar schema can also account for partial correction of SCID-ADA (Hirschhorn et al., 1996).

Figure 2.

A small number of transduced, γc-expressing T cell precursors can generate a fully diversified T cell repertoire. Transduced T cell precursors can divide ≥10 times before undergoing TCR B then A rearrangements. This process eventually generates a fully diversified TCR repertoire (as indicated by different colors of the T cells in the figure). For the sake of clarity, T cell differentiation has been simplified, and additional expansion/selection steps have been ignored. Red star shape indicates γc expression. Number of cells in the periphery is variable, indicating diversity in TCR clonal abundance. Horizontal bars with short branches indicate arbitrary representation of two distinct ISs of the retroviral vector. All progeny cells carry the same insertion.

Figure 3.

The three steps in the progress of gene therapy for SCID X1 (1999–2019). Step 1: First trial based on a γRV vector. Step 2: The LTR enhancer was removed from the vector while a promoter (elongation factor-1α) was inserted to drive IL2RG expression. Step 3: Usage of SIN LV vector instead of γRV should improve rate of transduction of HSC, thus correction of not only the T but also NK and B cell deficiency. Administration of low dose myeloablation (Busulfan) to the patient before autologous cell reinjection provides empty niches for relocalization of transduced HSC. Red text boxes indicate protocol modifications.