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Cellular benefits of gene therapy seen decades after treatment

LONDON (UK), March 2021 — An international collaboration between Great Ormond Street Hospital (GOSH), the UCL GOS Institute of Child Health (UCL GOS ICH) and Harvard Medical School has shown that the beneficial effects of gene therapy can be seen decades after the transplanted blood stem cells have been cleared by the body.

The research team monitored five patients who were successfully cured of SCID-X1 using gene therapy at GOSH. For three to 18 years, patients’ blood was regularly analyzed to detect which cell types and biomarker chemicals were present. The results showed that even though the stem cells transplanted as part of gene therapy had been cleared by the patients, the all-important corrected immune cells, called T-cells, were still forming.

Gene therapy works by first removing some of the patients’ blood-forming stem cells, which create all types of blood and immune cells. Next, a viral vector is used to deliver a new copy of the faulty gene into the DNA of the patient’s cells in a laboratory. These corrected stem cells are then returned to the patient in a so-called “autologous transplant,” where they go on to produce a continual supply of healthy immune cells capable of fighting infection.

In the gene therapy for SCID-X1, the corrected stem cells have been eventually cleared by the body but the patients remained cured of their condition. This team of researchers suggested that the cure was due to the fact that the body was still able to continually produce newly engineered T-cells – an important part of the body’s immune system. 

They used state-of-the-art gene tracking technology and numerous tests to give unprecedented details of the T-cells in SCID-X1 patients decades after gene therapy.

The team believe that this gene therapy has created the ideal conditions for the human thymus (the part of the body where T-cells develop) to host a long-term store of the correct type of progenitor cells that can form new T-cells. Further investigation of how this happens and how it can be exploited could be crucial for the development of next generation GT and cancer immunotherapy approaches. 

Luca Biasco, Ph.D., former faculty at Harvard Medical School and scientific affiliate of the gene therapy program at UCL GOS ICH, is a co-lead author of the research. “When we initially discovered that newly engineered T-cells were being actively produced in patients many years after receiving engineered stem cells, we were very excited,” he said. “We had predicted the existence of the long-term store of cells in the thymus that could turn into T-cells, but now we had the proof. 

“It has been incorrectly thought for some time that someone needs engineered stem cells in the bone marrow to produce new gene-corrected T-cells. We spent five years testing our hypothesis from every possible angle and we can now confirm that new T cells can be still generated for decades, even in the absence of stem cells.” 

He added that the technological platform the team set up for the direct tracking of viral-vector engineered cells in patients has a variety of applications, “from gene therapy to CAR-T cancer immunotherapy.”

Natalia Izotova, a Ph.D., student at UCL GOS ICH, is co-first author of the study. She noted that the team has already established new collaborations to build on their work “and we are hopeful that we will be able to identify and exploit these novel progenitor cells in the thymus to develop new and better treatment.”

Adrian Thrasher, M.D., Ph.D., professor of pediatric immunology at UCL GOS ICH and a co-lead author of the study, added, “The identification and exploitation of such long-term cell stores in the thymus could be crucial for the development of next generation gene therapy and cancer immunotherapy approaches.” 

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DOI: 10.1038/s41467-021-21834-9