Scientists from the Flaum Eye Institute have developed the first patient-derived human cell model of macular degeneration capable of forming drusen-like deposits. The model could help improve the understanding of disease pathogenesis and aid in the development and screening of new treatment options. Human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) were derived from healthy controls and patients with 3 genetic forms of macular dystrophy (MD): Sorsby’s fundus dystrophy, Doyne honeycomb retinal dystrophy/malattia Leventinese and autosomal dominant radial drusen. The amount and composition of drusen-like sub-RPE deposits were compared among the control and disease groups.

Reprogrammed hiPSC-RPE cells derived from MD patients developed more drusen-like sub-RPE deposits than those from healthy controls. Additionally, the deposits formed in an autonomous fashion in the absence of other retinal cells, choroidal circulation, or other exogenous factors. This in vitro behavior was observed for all 3 genetic forms of MD, suggesting RPE cell dysfunction could be central to multiple forms of the disease.

There was also increased levels of collagen type 4, an RPE-secreted basement membrane protein, in the extracellular matrix underlying the MD hiPSC-RPE cells.

As with every pre-clinical model, there are concerns about the applicability of the model to actual patients. By using patient-derived cells, however, there is hope that the models are more similar to actual human cells.

Although the study showed that drusen-like sub-RPE deposits can be produced by RPE cells alone, this model does not incorporate other important aspects of the human disease, such as the role of choroidal vasculature, retina, and Bruch's membrane, which may modulate the number and composition of the deposits.

Although there is no direct impact on my clinical practice at this point, the researchers are very hopeful that mechanistic studies on this model and future iterations of patient-derived hiPSC models will help us better understand the pathophysiology of drusen. These models could also aid in screening pharmaceutical agents, with the goal of preventing the end-stage manifestations of geographic atrophy and choroidal neovascularization.