X-linked severe combined immunodeficiency as a candidate disease for gene therapy.
| *Data from Kohn et al23; A. Fischer and M. Cavazzana-Calvo, personal communication in oral presentations, 2003 |
| Advantages |
| Complications and late failures after allogeneic transplantation mandate a search for better treatment. |
| Ex-vivo transduction: hematopoietic cells can be removed and enriched, cultured with retrovirus and then reinfused intravenously, where they will home to the bone marrow. |
| Disease gene product, the common gamma chain of cytokine receptors is widely expressed in blood lineages; overexpression apparently not harmful. |
| The problem of immune elimination of the corrected cells should not arise because of the immunodeficiency phenotype. |
| There is an in vivo selective advantage for lymphoid cells expressing the normal common gamma chain protein. |
| Animal models and human trials have been successful in restoring immunocompetence. |
| Of 10 infants given gene therapy as primary treatment in France by the group of Fischer et al, 9 had restoration of T-cell function.31,32 |
| Specific antibody production was restored in most. |
| A dose of > 1 million corrected CD34+ cells/kg was established as required to achieve full reconstitution. |
| Disadvantages* |
| Serious adverse events occurred in 2/10 infants: development of clonal leukemic proliferations of transduced cells. |
| Both were the youngest infants at treatment (1 and 3 months). |
| Clonal proliferations were detected about 2½ years after gene therapy. |
| The patients’ leukemic clones had different retroviral insertion sites, but both were near the 5′ end of the LIM domain only LMO-2 transcription factor gene. |
| Both patients have required chemotherapy, and the first received an allogeneic stem cell transplant. |
| Retrovirus vectors, chosen for their ability to effect permanent correction by integrating into the host chromosomal DNA, do not permit control of insertion site. |
| Possible harmful interactions between endogenous host factors (age, disease-specific effects, other inherited susceptibility genes, infections) and host genes whose expression is altered by nearby retroviral insertion (transcription factors, such as LMO-2) can combine to produce leukemia. |
| *Data from Kohn et al23; A. Fischer and M. Cavazzana-Calvo, personal communication in oral presentations, 2003 |
| Advantages |
| Complications and late failures after allogeneic transplantation mandate a search for better treatment. |
| Ex-vivo transduction: hematopoietic cells can be removed and enriched, cultured with retrovirus and then reinfused intravenously, where they will home to the bone marrow. |
| Disease gene product, the common gamma chain of cytokine receptors is widely expressed in blood lineages; overexpression apparently not harmful. |
| The problem of immune elimination of the corrected cells should not arise because of the immunodeficiency phenotype. |
| There is an in vivo selective advantage for lymphoid cells expressing the normal common gamma chain protein. |
| Animal models and human trials have been successful in restoring immunocompetence. |
| Of 10 infants given gene therapy as primary treatment in France by the group of Fischer et al, 9 had restoration of T-cell function.31,32 |
| Specific antibody production was restored in most. |
| A dose of > 1 million corrected CD34+ cells/kg was established as required to achieve full reconstitution. |
| Disadvantages* |
| Serious adverse events occurred in 2/10 infants: development of clonal leukemic proliferations of transduced cells. |
| Both were the youngest infants at treatment (1 and 3 months). |
| Clonal proliferations were detected about 2½ years after gene therapy. |
| The patients’ leukemic clones had different retroviral insertion sites, but both were near the 5′ end of the LIM domain only LMO-2 transcription factor gene. |
| Both patients have required chemotherapy, and the first received an allogeneic stem cell transplant. |
| Retrovirus vectors, chosen for their ability to effect permanent correction by integrating into the host chromosomal DNA, do not permit control of insertion site. |
| Possible harmful interactions between endogenous host factors (age, disease-specific effects, other inherited susceptibility genes, infections) and host genes whose expression is altered by nearby retroviral insertion (transcription factors, such as LMO-2) can combine to produce leukemia. |