A roadmap to the safe introduction of hESC in the clinic: the case of genetic mosaicism in hESC-derived retinal cells (FWOSB55)

Age-related macular degeneration (AMD) is the leading cause of blindness and vision impairment worldwide. The disease’s cause is age-dependent degeneration of the retinal pigment epithelium (RPE). The current treatments slow down the progression of the disease, but do not cure it. The most novel cell therapy to effectively cure AMD is based on the use of human pluripotent stem cell (hPSC) to make RPE for transplantation, and the first clinical trials yielded promising results. However, hPSC kept in culture acquire genetic abnormalities that may have pathogenic or oncogenic properties. This is one of the major current bottlenecks for the safe transition of these therapies to the clinic. In our study, we aim at providing knowledge on a specific aspect of genome instability: mosaicism, which refers to the fact that not all cells in the culture are genetically homogeneous. We will work with hPSC, hPSC-derived RPE and in vivo RPE from organ donor. We will study the genomic mosaicism of these cell types to assess if RPE inherit the genetic abnormalities from the hPSC, and how these compare to what is found in in vivo cells. Also, we will study the transcriptome of these cells at the single-cell level, and establish the impact of genetic abnormalities on the cells, including their malignant potential. This project will give researchers
and clinicians a roadmap for the correct screening of hPSC-derived tissues prior to transplantation.

Keywords:hESC