Reducing Rejection of Stem Cell-Derived RPE Grafts for Macular Degeneration

Abstract

Macular degeneration is a progressive disease of the retina and the leading cause of blindness worldwide, especially among those over 50 years of age in developed countries. There is not a cure available, and current therapies do not halt the progression of the disease. Early attempts to surgically treat macular degeneration with grafts of the retinal pigment epithelium (RPE) were unsuccessful, with some cases being attributed to human leukocyte antigen (HLA) mismatching causing rejection. Advancements in stem cell research enables a new tool to potentially treat macular degeneration. RPE has been successfully derived from human embryonic and human induced pluripotent stem cells. However, stem-cell derived RPE are capable of expressing both HLA class I and HLA class II molecules and are able to induce an immune response in the recipient due to HLA mismatching. Genetically engineering the stem cells to manipulating expression of HLA in the differentiated graft have been shown to reduce activation of immune cells. Furthermore, downregulating the expression of the Fas receptor may help to avoid immune system activation and increase cell survival. This approach has promising ramifications for treating macular degeneration and the field of stem cell therapy in general as it could help overcome the immune compatibility barrier of transplantation with donor grafts.