Stem cells as tools for studying the genetics of inherited retinal degenerations

Abstract

The ability to provide early clinical intervention for inherited disorders is heavily dependent on knowledge of a patient's disease-causing mutations and the resultant pathophysiologic mechanism(s). Without knowing a patient's disease-causing gene, and how gene mutations alter the health and functionality of affected cells, it would be difficult to develop and deliver patient-specific molecular or small molecule therapies. Many believe that the field of stem cell biology holds the keys to the future development of disease-, patient-, and cell-specific therapies. In the case of the eye, which is susceptible to an extremely common late-onset degenerative disease known as age-related macular degeneration, stem cell-based therapies could increase the quality of life for millions of patients worldwide. Furthermore, autologous, patient-specific induced pluripotent stem cells could be a viable source to treat rare Mendelian retinal degenerative diseases such as retinitis pigmentosa, Stargardt disease, and Best disease, to name a few.

Figure 1.

Schematic of the human retina. The major layers of the retina are shown schematically: NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium; BM, Bruch's membrane; and CV, choroidal vasculature. The photoreceptors, retinal pigment epithelium, and choroidal vasculature (indicated by red bracket on right of schematic) are the cell types that are most commonly affected by inherited retinal diseases.

Figure 2.

Relationship between knowledge of disease mechanism and disease progression on therapeutic options. Some therapeutic options are more suitable for earlier stages of disease than others. Similarly, some require a precise understanding of the cause and/or mechanism of the disease, whereas others are more generally usable.

Figure 3.

Schematic depiction of the 10q26 risk haplotype and associated mutations.