Gene therapy of primary immunodeficiencies: experimental approach and preliminary clinical results

Primary immunodeficiencies have been long considered as a possible experime ntal field for gene therapy. Adenosine deaminase (ADA) deficiency was the f irst inherited disease for which clinical gene therapy was performed. Infus ion of T cells in which the ADA gene had ben retrovirally transfered, led t o sustained detection of transduced and functional T cells at least in 2 ca ses. ADA gene transfer into CD34 hematopoietic precursor cells was less suc cessful although detection of transduced T cells 4 years after gene transfe r has been reported. The low number of transduced T cells, however, was not sufficient to provide clinical benefit. Many factors could have influenced the outcome of these clinical studies, including partial loss of expected selective advantage caused by concomitant PEG-ADA therapy and, obviously, l imitations of presently available murine-derived retroviral vectors to tran sduce human cells. Possible applications of gene transfer to the treatment of other forms of SCID including gc and JAK-3 deficiency are herein discuss ed based on encouraging in vitro and in vivo experimental results. It is li kely that advances in vector technology and/or hematopoietic stem cell mani pulation will be required to improve transduction efficiencies in hopes of achieving significant clinical benefits of gene therapy for the many primar y immunodeficiencies. This will be particularly important for situations in which transgene expression will not confer a selective growth on survival advantage, as for instance in functional deficiencies in phagocytic cells.