What locus does SCID sffect trial#

E.) 437–474 (Cold Spring Harbor Laboratory Press, New York, 1997).īaum, C., Ostertag, W., Stocking, C. Durability of transgene expression and vector integration: recombinant SV40-derived gene therapy vectors. Site specific integration by adeno-associated virus. AAV serotype 2 vectors preferentially integrate into active genes in mice. A modest preference was seen for integration into gene-rich regions that were actively transcribed. A paper that catalogued more than 500 independent genomic integration sites of HIV in human cells. HIV-1 integration in the human genome favors active genes and local hotspots. Retrovirus integration and chromatin structure: Moloney murine leukemia proviral integration sites map near DNase I-hypersensitive sites. Acceptor sites for retroviral integrations map near DNase I-hypersensitive sites in chromatin. Gene therapy for genetic and haematological disorders and immunodeficiency. The use of tissue-specific, regulated transcription units should, in principle, diminish the risk of proto-oncogene transactivation. It might be possible to develop retroviral vectors or other gene-therapy methods that are less likely to lead to insertional oncogenesis and still retain the therapeutic benefits. These include the high level of engraftment and expansion of the genetically modified cells, unique properties of the haematopoietic stem and progenitor cells in bone marrow of X-linked SCID patients, the immune deficiency of the X-linked SCID patients and/or the transferred gene itself.įurther use of current gene-transfer methods for the treatment of SCID poses an ethical dilemma in the consideration of the complex benefits and risks. Multiple factors could have contributed to the development of leukaemia in the patients involved in this trial. Leukaemia has been linked to vector integration in only one mouse study using this approach. The complication of leukaemia has not occurred in any other clinical trial, nor in any large animal model that used retroviral vectors to modify haematopoietic stem cells. This cancer seems to be caused by retroviral-vector activation of a cellular oncogene at the site of integration, a process known as 'insertional oncogenesis'. Two subjects developed T-cell leukaemia more than 2 years after gene therapy commenced.

What locus does SCID sffect trial#

Gene therapy for blood-cell diseases can be performed with retroviral vectors that insert into the genome of haematopoietic stem cells.Ī recent trial of gene therapy for infants with X-linked severe combined immune deficiency (XSCID) successfully restored the immune systems of most subjects.