Gene therapy offers severe combined immunodeficiency hope
MedWire News: Inserting a corrected adenosine deaminase (ADA) gene into bone marrow cells of individuals with severe combined immunodeficiency (SCID) may help to restore normal autoimmune response, study findings show.
Defective ADA genes underlie many cases of SCID and are associated with the defective B cell tolerance that can occur in ADA-SCID patients. But the current findings show that this could be corrected by hematopoietic stem cell gene therapy (HSC-GT), explain the authors.
Alessandro Aiuti (San Raffaele Telethon Institute for Gene Therapy, Milan, Italy) and co-authors say that HSC-GT presents an alternative management solution to the conventional strategies of enzyme therapy and bone marrow transplant.
In the study, bone marrow cell samples were taken from three patients with ADA-SCID. Abnormal autoimmune responses were noted in the transitional B cells present in these samples. On further observation, these cells developed into mature naïve B cells that displayed a high level of autoreactivity to the body's antigens.
Writing in the Journal of Clinical Investigation, Aiuti et al explain that "autoreactive B cells are normally removed at two distinct checkpoints, first in the bone marrow and then in the periphery."
The observations made prior to HSC-GT therefore indicate that faulty ADA genes may prevent correct functioning of these checkpoints.
When a corrected version of the ADA gene was inserted into the bone marrow cells of the patients, B cell tolerance was found to be restored to near-normal levels and correct removal of autoreactive B cells was noted.
Although it is unclear why abnormal ADA genes lead to atypical B cell tolerance, Eline Prak (University of Pennsylvania, Philadelphia, USA) puts forward a hypothesis in a related commentary.
She says: "Altered signaling could fail to trigger the central B cell tolerance mechanisms of receptor editing or apoptosis, reducing the counter-selection of autoreactive clones."
Aiuti and team highlight that although HSC-GT improved B cell tolerance, it did not restore it to complete normality.
They therefore conclude: "Modification of the preparatory regimen or increased gene transfer efficiency by more robust approaches, such as lentiviral vectors, may further improve HSC-GT outcome."
By Lauretta Ihonor