Gene therapy for human severe combined immunodeficiencies. (2002)

Besides long-term analysis of treated cases, there is an obvious need to reproduce these results in a larger set of patients, including more cases in whom an endogenous abnormal γc protein is present in lymphocyte precursors as well as patients with partially preserved T cell development (Notarangelo et al., 2000xNotarangelo, L.D., Giliani, S., Mazza, C., Mella, P., Savoldi, G., Rodriguez-Perez, C., Mazzolari, E., Fiorini, M., Duse, M., Plebani, A. et al. Immunol. Rev. 2000; 178: 39–48Crossref | PubMedSee all References(Notarangelo et al., 2000). Also, and this is not a straightforward issue, methods for the large-scale production of clinical batches of vectors have to be developed. What about extension to the treatment of other immunodeficiencies? If one assumes that the most suitable disease was chosen, then treatment of other conditions raises additional difficulties (for a detailed discussion of the latter, see Candotti 2000xCandotti, F. Pediatr. Clin. North Am. 2000; 47: 1389–1407Abstract | Full Text | Full Text PDF | PubMedSee all References, Fischer et al. 2000xFischer, A., Hacein-Bey, S., Le Deist, F., Soudais, C., and Di Santo, J. Immunol. Rev. 2000; 178: 13–20Crossref | PubMedSee all References). This means that further advances in gene transfer technology in hematopoietic precursor cells will be necessary in this setting. Note, however, that for the treatment of conditions for which a selective advantage of transduced cells is expected, a high rate of CD34 (+) cell transduction might not be appropriate since: (1) a high rate of transduction is not necessary to achieve T lymphocyte development and (2) it will lead to the multiplication of the number of transgene copy integrations. The latter could potentially increase the risk of deleterious consequences of insertional mutagenesis. SCID conditions with an identical or closely related disease mechanism to SCID-X1, i.e., JAK-3 and IL-7Rα deficiency, are the most obvious next candidate diseases for gene therapy. Experimental gene therapy of JAK-3(-) mice has provided convincing results including proven efficacy in unirradiated mice (Bunting et al., 2000xBunting, K.D., Lu, T., Kelly, P.F., and Sorrentino, B.P. Hum. Gene Ther. 2000; 11: 2353–2364Crossref | PubMed | Scopus (33)See all References(Bunting et al., 2000). SCID conditions caused by Rag-1, Rag-2, or Artemis gene mutations are also worthwhile to consider, since allogeneic stem cell transplantation provides poorer results than for other SCID conditions. Genetic deficiencies in the immune system that impair further downstream T cell development will be more difficult to tackle since (1) a less potent selective advantage is to be expected and (2) considerations on transgene expression regulation (both spatial and temporal) will have to be addressed. In this respect however, the spectacular achievement of tissue-specific β-globin expression in erythroid cells in β thalassemic mice represents a significant advance. This result is based on the insertion in the lentiviral vector of a minimal version of the locus control region (LTR) of the β-globin gene (May et al., 2000xMay, C., Rivella, S., Callegari, J., Heller, G., Gaensler, K.M., Luzzatto, L., and Sadelain, M. Nature. 2000; 406: 82–86Crossref | PubMed | Scopus (372)See all References(May et al., 2000).One can, from the above, consider that proof of principle has been achieved in the genetic treatment of inherited disorders of the immune system. Much remains to be done by combining both an in depth appraisal of every single disease mechanism (i.e., in other words, understanding the function of the corresponding gene product) and development of new aspects in gene transfer technologies. It is obvious that a potentially safe use of lentiviral vectors able to efficiently target HSC would provide a major advance to the field (reviewed in Sadelain et al., 2000xSadelain, M., Frassoni, F., and Riviere, I. Curr. Opin. Hematol. 2000; 7: 364–377Crossref | PubMed | Scopus (20)See all ReferencesSadelain et al., 2000). Technologies of gene repair might also become a consideration in the future.