Gene therapy of severe combined immunodeficiencies

Abstract

Many of the primary immunodeficiency diseases (PID) are characterized by a susceptibility to recurrent and devastating infections as well as to other severe immunopathological consequences such as autoimmune manifestations. Therefore, these PID can lead to premature death following months or years of debilitating complications. Defects of the T lymphocyte lineage and to some extent of innate immunity represent the most severe forms of PID. Nevertheless, progress has been made in treatment. For more than 30 years, hematopoïetic stem cell transplantation has been successfully utilized to firstly treat severe combined immunodeficiencies (SCID). More recently, a variety of other PID conditions have been treated using this approach. Further progress in the control of infections has resulted in a very high chance of cure for SCID patients who have an HLA identical sibling. Results of T-depleted stem cell transplantation from alternative donors have been used since the early 80’s and led to the survival of more than half of the transplanted patients with SCID. The European survey indicates an overall 60% rate of survival while a recent work from Duke University reported a 78% survival. These limitations of stem cell transplantation as a treatment of SCID conditions have prompted efforts to establish an alternative option including gene therapy. Because allogeneic stem cell transplantation can cure genetic disorders of the lymphoid system, it is suggested that, in principle, correction of autologous progenitors cells could also work. Correction of an inherited disorder by gene therapy implies firstly gene identification. More than 6 genes, mutations of which are responsible for PID, have been identified including SCID conditions and another 8 severe T cell deficiencies. However, a number of considerations have to be envisaged for each disease. They include disease mechanism, potential selective advantage conferred to transduced cells, temporo-spatial pattern of expression of the gene. Therefore, risks of aberrant transgene expression and possible overexpression as a function of the gene product should be assessed. Finally, the fact that a mutated product could exert a transdominant negative effect should also be tested.