Navitoclax restored hematopoietic stem cell function in mice with sickle cell disease
Navitoclax restored hematopoietic stem cell function in mice with sickle cell disease
On 22 July, Science Translational Medicine published a study of hematopoietic stem cells in sickle cell disease. In mice, navitoclax restored the number of functional cells and their ability to reconstitute hematopoiesis after transplantation. In patient cells studied outside the body, the drugs improved colony formation.
Gene therapy for sickle cell disease begins with the patient’s own hematopoietic stem cells. These cells are collected, their DNA is modified or a functional gene is introduced, and they are returned to the patient after bone marrow conditioning. The cells must then engraft in the bone marrow and produce new blood cells for years. A genetic construct is useless if the cell does not survive processing and engraft after transplantation.
The St. Jude team studied these cells in mice and in samples from people with sickle cell disease. The disease forces the bone marrow to continually replace damaged red blood cells. In hematopoietic stem and progenitor cells, the authors found oxidative stress, DNA damage, and signs of senescence, a state in which a cell no longer divides or functions normally. In the mouse model, the bone marrow contained fewer functional long lived cells. Human cells studied outside the body were less able to form colonies, which are groups of descendants derived from a single cell.
The researchers then treated the cells with navitoclax, a drug used in this study to target cells showing signs of senescence. In mice, treatment restored stem cell numbers and the ability of transplanted cells to populate the bone marrow. In patient samples, either navitoclax or a combination of dasatinib and quercetin improved colony formation.
Senescence may reduce the quality of the starting material used for gene therapy. The authors propose testing whether treating stem cells with senolytics can improve the quality of the cellular product before autologous editing, in which patients receive their own modified cells.