Stephanie Cherqui, PhD
Scripps Research Institute, San Diago, USA.
Cystinosis is a metabolic hereditary disease characterized by the accumulation of cystine in most of the patient’s tissues leading to multiple organ dysfunction. The curative treatment of such hereditary diseases requires the progressive replacement of the dying cells by cells expressing the lacking gene (CTNS) in multiple tissue compartments. We chose to use stem cells as a therapeutic strategy for cystinosis because of their versatility and plasticity. Three types of bone marrow cells can be used for clinical application: whole bone marrow cells (BMC), hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC).
Using the murine model for cystinosis, Ctns-/- mice, we tested these three types of cells on cystinosis. The transplanted cells were from wildtype mice and therefore expressed a functional Ctns gene. MSC did not integrate efficiently in any organ and did not have any positive impact on the disease. In contrast, we showed that organ-specific cystine content was dramatically reduced (80% reduction in average) in all organs tested in the BMC and HSC-treated mice. Renal dysfunction was prevented and depositions of corneal cystine crystals were improved as compared to the controls. Confocal microscopy and quantitative PCR revealed the presence of a large quantity of transplanted BMC and HSC expressing Ctns in all organs tested. This abundant stem cell-derived cells engraftment in all the tissues was surprising and highlights the efficiency of this strategy for a chronic, progressive degenerative disease. Therefore, adult bone marrow stem cell therapy, specifically BMC or HSC transplantation, is particularly well suited as a potential treatment for cystinosis.
Our long-term objective is to isolate HSC from the bone marrow of patients, genetically modify them ex vivo to introduce the defective gene (CTNS) and inject them back into the patients. This will create a reservoir of healthy stem cells in the bone marrow that can migrate to and integrate in the different organs as a function of the progressive tissue damage for the life of the patient. Therefore, our next series of planned studies will test, in the mouse model for cystinosis, the most efficient and safest viral vector to transduce HSC to introduce a functional CTNS gene.