The Kohn group at UCLA has created lentiviral vectors expressing FoxP3 or IL-10 for transduction into patient hematopoietic stem cells (HSC). Successful transplantation of autologous HSCs would allow for treatment of a number of auto-immune and auto-inflammatory diseases, while avoiding complications associated with allogenic transplants or autologous T cell therapies.
A number of auto-immune and auto-inflammatory diseases, as well as genetic deficiencies of FoxP3 (IPEX disease) or IL10 could be treated with an allogenic hematopoietic stem cell transplantation (HSCT) to provide a source of normal stem cells that differentiate into populations of the immune effector cells with the needed FoxP3 or IL-10 gene products. However, allogeneic HSCTs are limited by the need for a well-matched donor and risk of graft rejection or diseases due to immunological disparities between donor and recipient. Alternatively, autologous T cells from patients may be modified with vectors expressing FoxP3 or IL-10 with constitutive promoters, but these T cells have a finite life-span in vivo and the effectiveness of the treatment may decrease with time. One way to avoid complications with allogenic HSCT or T cell transplants is to reintroduce autologous HSC with genetic corrections in FoxP3 or IL10. Therefore, an effective, stable vector that allows for the FoxP3 or IL10 expression in HSCs would avoid these immune complications and allows far more effective HSCTs.
The Kohn group at UCLA has successfully developed lentiviral vectors compatible with human hematopoietic stem cells that uses endogenous gene elements to regulate physiologic gene expression of FoxP3 and IL10. These vectors can be transduced into autologous HSCs to treat genetic deficiencies of FoxP3 (IPEX disease) or IL-10 (auto-inflammatory conditions). These genetically altered HSCs can also be used to treat other auto-immune and auto-inflammatory conditions (e.g. inflammatory bowel disease, Type 1 diabetes mellitus, multiple sclerosis, etc.). In contrast to gene transfer vectors that would use non-specific enhancer/promoters to drive constitutive expression of these genes, which could lead to ectopic expression in multiple blood cell types and lead to unwanted effects, the use of the endogenous transcriptional control elements lead to precise, accurate on-target expression of the genes to mimic normal patterns of expression.
Stem cells, hematopoietic stem cells, HSC, stem cell transplant, HSCT, auto-immune, autoimmune, auto-inflammatory, autoinflammatory, IPEX disease, inflammatory bowel disease, Type 1 diabetes mellitus, multiple sclerosis