The benefits of hematopoietic stem cell (HSC) gene therapy can be seen for decades after treatment. This news comes from a study of patients with X-linked severe combined immunodeficiency (SCID-X1) who received autologous transplanted blood stem cells that had long cleared the body. A genetically caused immune system disorder, SCID-X1 is caused mutations in the interleukin 2 receptor common gamma chain (IL2RG), which is located on the X-chromosome.
Infants with SCID-X1—who are almost exclusively male—fail to develop two major classes of immune system cells, T cells and NK cells, with normal numbers of dysfunctional B cells.
Five patients with the disease were treated using gene therapy with a viral vector to repair the faulty IL2RG gene. The corrected version of the stem cells were delivered to the patients who were followed between 3-18 years. Analysis of their blood samples looked for the types of cells present, along with various biomarkers of disease over time. The results showed that even though the stem cells transplanted as part of gene therapy had been cleared by the patients decades after treatment, functionally normal T-cells still developed and patients remained cure of SCID-X1.
“Decades after treatment, we can still detect and analyze transduced naïve T cells whose production is likely maintained by a population of long-term lymphoid progenitors,” the authors write.
The researchers were able to track the fate of transplanted cells for the first time in vivo in humans by integration site clonal tracking. In gene therapy with human hematopoietic stem and progenitor cells, each gene-corrected cell and its progeny are marked in a unique way by the integrating vector, including the presence of semi-randomly integrated vector sequences. This allows researchers to track the cells’ lineage in blood samples and using DNA sequencing to find the vector integration sites.
In this analysis, after tracking insertional clonal markers over time in the blood samples of treated patients, the researchers observed that these progenitors lead to development of both T and NK cells for up to 19 years after gene therapy. Further, the patients lacked the vector-positive myeloid/B cells indicating absence of engineered stem cells.
“Our data provide the first formal evidence in vivo in humans that de novo production of genetically engineered T and NK cells maintained by long-term lymphoid progenitors surviving many years after loss of transplanted HSC,” the authors write. “The absence of genetically engineered HSC in these individuals is inferred on the basis of the consistent lack of vector-positive circulating myeloid and B cells and is consistent with the fact that no myelosuppressive bone marrow conditioning was administered.”
While the team did not find provide evidence how this long-term result was achieved, they believe the main benefit derived from patients’ ability to continually produce newly-engineered T cells. They suspect that gene therapy may create conditions in the thymus, where T-cells develop, that support a long-term supply of the corrected progenitor cells. Further investigation of how this happens and how it can be exploited could be crucial for the development of next generation gene therapy and cancer immunotherapy approaches.