GMP-Compliant Human ES-Derived RPE Cells Rescue Vision in Mouse Models of Macular Degeneration

Abstract

Purpose: : Stargardt’s macular dystrophy is one of the most frequent forms of juvenile macular degeneration. It is characterized by progressive accumulation of lipofuscin in the retinal pigment epithelium (RPE), which leads to atrophy of RPE cells and followed by photoreceptor death. There is no treatment available yet. Age-related macular degeneratio is the leading cause of blindness in older individuals and shares some pathogenic similarities. The presence of animal models, particularly rodents with diseases homologous or analogous to human disorders, allows investigators to explore therapeutic approaches that might eventually be applied for human diseases. Cell-based therapy for eye disease has been shown very effective in limiting the progress of retinal degeneration and in rescuing vision. Here we examine Good Manufacturing Practice (GMP)-compliant human ES-derived pigmental epithelium (hES-RPE) cells in rescue vision in mouse modesl of macular degeneration.

Methods: : Both ElovL4^+/- (TG3) (University of Utah) and Ccl2^-/- (Jackson laboratory) mice received subretinal injections of human embryonic stem cell-derived RPE cells (50,000/eye) manufactured under GMP-compliant condition; medium alone and untreated eyes were used as control. All animals were maintained under oral cyclosporine A administered in the drinking water. The animal's acuity was tested 2 weeks, 4 weeks, 6 weeks and 8 weeks after surgery by optomotor responses. Morphologically, we examined the donor cell distribution by human-specific antibodies, and the relationships between donor cells and cells of the host retina, as well as looked for untoward pathological events.

Results: : At all time points studied, cell-grafted animals performed consistently better than sham and unoperated animals by the optomotor test. Histological study demonstrated that there is no sign of tumor formation or untoward pathological events.

Conclusions: : This is the first study that indicates cell-based therapy can rescue visual function in mouse models of macular degeneration. This adds to the value of human embryonic stem cell-derived RPE cells as a potential therapy for macular degeneration.

Keywords: age-related macular degeneration • visual acuity • transplantation