Abstract
For the last 35 years or so, allogeneic hematopoietic stem cell transplantation (HSCT) has been the only curative approach for patients affected by severe combined immunodeficiencies (SCID), a medical emergency. According to the most recent European survey haploidentical transplants allow a survival rate at 3 years of 75% (taking only into account patients transplanted since 1995). The mortality rate is heavily influenced by age at transplantation (being very low within young infants), in correlation with the infection burden and also the incidence of acute graft-versus-host reaction (GVHD). Between 1998 and 2003, 6 patients with NK(−) B(+) SCIDs (either gc or JAK3 deficiency) received an haploidentical HSCT at Necker Hospital, 3 of them died from an infection, one in the context of a severe GVHD. In addition, despite the improvement in the survival rate, over the time a number of long-term concerns have been detected including a frequent persistence of a B cell deficiency, and a decline in T-cell functions related to the absence of donor stem cell engraftment and may be also to a premature decline in the thymus function.
Therefore, several patients have received a second transplant with a low efficiency in an haploidentical setting.
These significant limitations set the rationale for the development of an alternative strategy such as gene therapy. From March 1999 up to May 2002, ten children with gc deficiency under the age of one year were enrolled.
All of them are alive today. The gc gene transfer into patients’ CD34(+) cells led in 9 out of 10 patients to the emergence of T and NK lymphocytes. It took 10 to 12 weeks to detect mature T cells in the periphery, a delay which is significantly faster than the one observed after haploidentical HSCT. In all but 2 patients, T cell counts normalized up to 5.3 years after gene therapy. The occurrence of two severe adverse events led to put transiently the trial on hold in order to understand the pathophysiology of these events and assess its overall risks. Following a thorough analysis of the retrospective data and a prospective analysis, it was concluded that the benefit/risk balance in favor of the gene therapy approach at least for patients older than 3 months, hence our gene therapy protocol has been reopened. An update of the clinical data will provided at the meeting.
Gene Therapy for Human Severe Combined Immunodeficiencies
