Eye model may solve the mystery of macular degeneration’s cause

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A new three-dimensional lab model mimics the part of the human retina affected in macular degeneration.

The research could be an important breakthrough in the quest for an age-related macular degeneration (AMD) cure.

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.

The new model combines stem cell-derived retinal tissue and vascular networks from human patients with bioengineered synthetic materials in a three-dimensional “matrix.” Notably, 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 researchers have also demonstrated that wet-AMD-related changes in their human retina model could be targeted with drugs.

“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, an associate professor of ophthalmology at the University of Rochester’s Flaum Eye Institute.

The lab of Danielle Benoit, professor of biomedical engineering and director of the materials science program, engineered the synthetic materials for the matrix and helped configure it, as described in a paper in Cell Stem Cell.

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 other “systemic issues,” for example, in blood supply, cause the disease.

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.

AMD affects two areas of the human eye. 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 choriocapillaris layer 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,” Singh says.

And that’s why Benoit’s lab, which specializes in creating synthetic hydrogels for cell culture, tissue engineering, and target drug delivery, was important.

Benoit’s lab engineered the 3D matrix in which the choriocapillaris could be safely placed and also “properly oriented in the overall vasculature,” Benoit says. “We also facilitated the adhesion of the RPE cells within the model. It was a small, but important contribution. A three-dimensional model was essential to describe the really amazing things that have been identified and discovered using this model.”

The findings offer a possible resolution to the debate over the causes of macular degeneration. The researchers now show for the first time that defects in RPE cells alone are sufficient to cause the disease. “You can have completely normal choriocapillaris, but if your RPE’s are dysfunctional it will cause the choriocapillaristo dysfunction,” Singh says.

Similarly, using blood samples from patients with wet AMD in the human retina model, their data for the first time also shows that blood-derived factors from patients can independently contribute to the development and progression of wet AMD.

The collaborations, Singh says, have succeeded in:

  • Creating an accurate human model of the RPE/choriocapillaris complex
  • Confirming that RPE and mesenchymal stem cells play a role in the development of the choriocapillaris layer
  • Mimicking aspects of macular degeneration in the human model
  • Understanding the role of specific cells types and blood-derived factors in the development of macular degeneration
  • Targeting the disease, using a drug in a patient derived cell model

Additional researchers from the University of Rochester, the University of Wisconsin, and the Cleveland Clinic Cole Eye Institute contributed to the work.

Funding support came from the National Institutes of Health, BrightFocus Foundation, Foundation of Fighting Blindness, Knights Templar eye foundation, and the Retina Research Foundation and Research to Prevent Blindness.

Source: University of Rochester

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Kathy Laura

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