Researchers have discovered a drug already used in cancer patients that, when used in current gene therapy protocols, can improve the function of blood stem cells by three-fold.

Every day, a trillion blood cells are produced in the human body. Blood stem cells are the only cell types in our body that can produce all blood cell types over the course of our lives, giving them enormous regenerative potential.

Gene therapy using blood stem cells is a groundbreaking treatment that currently offers the only cure for over ten life-threatening genetic diseases and has already saved the lives of over two million people with blood cancer and other diseases.

These therapies involve taking blood stem cell samples from patients whose genetic defect is corrected in a dish before being reintroduced into the patient. However, blood stem cell therapies continue to face limitations due to the durability of the cells outside the body. When removed from their environment in the human body and cultured in a dish, most blood stem cells lose their function. The exact timing and cause of this loss of function have not been well understood.

Now scientists from the Laurenti Group and other researchers at the Cambridge Stem Cell Institute (CSCI) and the Department of Haematology at the University of Cambridge have established a timeline for blood stem cells under current gene therapy protocols, which typically last three days. After the first 24 hours in a dish, more than 50% of blood stem cells are unable to sustain lifelong blood production, before therapy would even begin in a clinical setting.

During these first 24 hours, the cells activate a complex molecular stress response to adapt to the dish. By studying this stress response, the team found a solution. By repurposing a cancer growth blocker (ruxolitinib) already used to treat cancer, they were able to increase stem cell function threefold in a dish.

The group’s goal is now to modify current gene therapy protocols to include this drug. This will enable patients to receive as many high-quality blood stem cells as possible and improve their chances of success.

The study appears today in Blood Diary.

Professor Elisa Laurenti, from the University of Cambridge’s Stem Cell Institute and lead author of the study, said: “This is really exciting because we are now able to understand the enormous stress that these stem cells feel when they are manipulated outside of our bodies. Biologically, this is really fascinating because it affects every aspect of their biology. Fortunately, we have been able to identify an important molecular pathway that controls many of these responses and that can be targeted by a drug that is already in use and safe to use.

“I hope that our findings will enable safer treatment of gene therapy patients. Our discovery also opens up many possibilities for better ex vivo proliferation of blood stem cells and broadening the range of diseases in which we can use blood stem cells to improve patients’ lives.”

Dr Carys Johnson of the University of Cambridge’s Stem Cell Institute and lead author of the study said: “Although we expected that taking these cells out of the body and culturing them on a plastic surface would change gene expression, the extent of the change we found was surprising: over 10,000 genes were altered and a significant stress response was observed. Also striking was the discovery that the majority of blood stem cells lose their function during gene therapy before they are transplanted back into the patient.”

“We have identified an important bottleneck where function is being lost and clinical culture could be improved. I hope our work will drive advances in culture protocols to better harness the power of blood stem cells and improve the safety and efficacy of clinical approaches.”