Age-related macular degeneration (AMD), which leads to a loss of central vision, is the most frequent cause of blindness in adults 50 years of age or older, affecting an estimated 196 million people worldwide. There is no cure, though treatment can slow the onset and preserve some vision.
Researchers at the University of Rochester report that they have made an important breakthrough in the quest for an AMD cure. Their first three-dimensional (3D) lab model mimics the part of the human retina affected in macular degeneration.
Their model combines stem cell-derived retinal tissue and vascular networks from human patients with bioengineered synthetic materials in a 3D matrix. Using patient-derived 3D retinal tissue allowed the researchers to investigate the underlying mechanisms involved in advanced neovascular macular degeneration—the wet form of macular degeneration—which is the more debilitating and blinding form of the disease.
The scientists, who published their study (“3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration”) in Cell Stem Cell, have also demonstrated that wet-AMD-related changes in their human retina model could be targeted with drugs.
“The retinal pigment epithelium (RPE)-choriocapillaris (CC) complex in the eye is compromised in age-related macular degeneration (AMD) and related macular dystrophies (MDs), yet in vitro models of RPE-CC complex that enable investigation of AMD/MD pathophysiology are lacking. By incorporating iPSC-derived cells into a hydrogel-based extracellular matrix, we developed a 3D RPE-CC model that recapitulates key features of both healthy and AMD/MD eyes and provides modular control over RPE and CC layers,” write the investigators.
“Using this 3D RPE-CC model, we demonstrated that both RPE- and mesenchyme-secreted factors are necessary for the formation of fenestrated CC-like vasculature. Our data show that choroidal neovascularization (CNV) and CC atrophy occur in the absence of endothelial cell dysfunction and are not necessarily secondary to drusen deposits underneath RPE cells, and CC atrophy and/or CNV can be initiated systemically by patient serum or locally by mutant RPE-secreted factors.
“Finally, we identify FGF2 and matrix metalloproteinases as potential therapeutic targets for AMD/MDs.”
“Once we have validated this over a large sample, the next hope would be to develop rational drug therapies and potentially even test the efficacy of a specific drug to work for individual patients,” says Ruchira Singh, PhD, an associate professor of ophthalmology at the University’s Flaum Eye Institute.
The lab of Danielle Benoit, PhD, professor of biomedical engineering and director of the Materials Science Program, engineered the synthetic materials for the matrix and helped configure it. Singh says the findings should help resolve a “huge” debate among researchers in the field who have been trying to determine whether defects in the retina itself are responsible for the disease (and if so, which parts of the retina are responsible), or the disease is caused by other “systemic issues,” for example, in blood supply.
Their research points strongly to retinal defects as being responsible—and in particular, to defects in an area called the retinal pigment epithelium (RPE), a pigmented cell layer that nourishes the retina’s photoreceptor cells.
Importance of 3D model
Two areas of the human eye are affected by AMD. They include the RPE and, beneath the RPE, an underlying support system called the choriocapillaris, composed largely of capillaries that feed the outer retina.
Until now, researchers have relied largely on rodent models. But the anatomy and physiology of the human and rodent retinae are very different. According to Singh, it was essential to create “an in vitro human model of the choriocapillaris layer integrated with the RPE to get the entire complex that is affected by this disease.”
For example, in a previous study, Singh’s lab used only a single retina cell type—patient-derived retinal pigment epithelium (RPE)—to show that symptoms of early and dry forms of AMD could be mimicked in culture and could be solely caused by dysfunction in the RPE cells. However, the role of the choriocapillarislayer had remained “a mystery that nobody has ever been able to model in culture,” she says.
That’s why it was so important to develop an in vitro and modular human model that could integrate a choriocapillaris layer with the RPE “to get the entire complex that is affected by this disease, so that properties of each individual cell type can be controlled independently,” points out Singh.
