Researchers from the laboratory of David Gamm, who is the director of the University of Wisconsin McPhearson Eye Research Institute have made patient-specific pluripotent stem cells to study and model an eye disease known as age-related macular degeneration.
Gamm and his colleagues focused on a rare eye disease called Best disease for their work. Best disease is also known as “vitelliform macular dystrophy,” and it is an inherited disease of the eye. Best disease is inherited as an “autosomal dominant” disease, which means that you only need one copy of the chromosome that carries the gene responsible for the disease to show symptoms and it occurs equally in males and females. The disease first makes its appearance in childhood, and results from abnormalities in the tissue in the very back of the eye, behind the neural retina; the retinal pigment epithelium (RPE).
Patients with Best disease show dysfunction of a protein called “bestrophin” and this messes up ion transport in the RPE cells. The result is abnormal accumulation of fluid and other rubbish in the RPE cells and in the space between the RPE and the neural retina. The accumulation of all this junk kills off photoreceptors in the neural retina and the patient’s vision goes south rather quickly.
Gamm wanted to construct a model system for Best disease, which such a model would also tell him more about age-related macular degeneration, which is the main cause of blindness in people over 50. To make his model, Gamm took skin cells from patients with Best disease and made induced pluripotent stem cells (iPSCs) from them. Once the iPSCs were established in culture, Gamm differentiated the stem cells into RPE cells.
Gamm had made iPSCs from patients with Best disease and siblings of the patients who did not have Best disease. The cultured RPEs made from iPSCs derived from Best disease patients displayed many of the features of RPEs in the eyes of patients with Best disease. The retinas of Best patients contain fluid-filled spots that have the appearance of scrambled eggs.
Gamm’s cultures RPE’s from Best patients showed this same pathology whereas the RPEs from patients without Best disease failed to show such changes. The cultured RPEs showed other abnormalities that had never been detected to date in retinal cells from Best patients. For example, one of the jobs of the RPE cells is to help recycle used visual pigments. The RPE cells engulf and digest disc-like vesicles that bud from the photoreceptors and degrade the materials in them. However, cultured RPEs from Best patients were slow to degrade visual pigments, and showed abnormalities in their calcium signaling and handling various types of cellular stresses.
According to Gamm, “This model gives us a chance to understand the biological effects of human gene mutations in a relatively expeditious manner. Continuing, Gamm said: “Ultimately, we hope the model will help us craft treatments to slow or reverse the course of Best disease.”
Hopefully, Gamm and other eye researchers can use a model such as Gamm’s to develop and refine treatments for such degenerative eye diseased. Gamm said that his “results give us some ideas where to look for therapies that would allow us to interfere with the disease process. And the stem cell model gives us a chance to test those therapies before trying them on patients.”
There is a human dimension to this work, since the patients who volunteered to provide the tissue for these experiments feel as though they are participating in helping develop a treatment that has plagued them for some time.
As Gamm said, “These family members know they’re not getting treated directly as a result of this study, but they’re doing it out of concern for the next generation. That brings peace to them, to know that they’re not passive victims of this disease, but instead, active players in the discovery process.”
This technique could almost certainly provide ways to make model systems for other types of eye diseases.