Grant: Project Grant

Visual perception starts in the retina, where photoreceptor cells transform light into electrical signals that can be interpreted by the brain. In retinal degenerative diseases like retinitis pigmentosa, macular degeneration or glaucoma, the progressive loss of neurons eventually leads to blindness. Unfortunately, these cells cannot be naturally replaced, such that these diseases remain incurable and represent a major burden for the patients, their family, and the health system. While some gene therapy and neuroprotective strategies are advancing in the clinic, these approaches can only act on remaining retinal cells and are thus ineffective when these cells have already been lost. Transplantation of stem cell-derived retinal neurons offer hope for vision restoration, but the very poor integration in the host tissue remains a major obstacle. It is therefore urgent to develop alternative strategies. One promising approach that emerged in recent years is the direct conversion (reprogramming) of a type of cells called glia, which are spared in disease, into retinal neurons that are lost in various retinal dystrophies. This approach circumvents the need for complicated transplantation surgeries and provides a potential way to restore vision, even in advanced stages of disease. In recent years, we have identified gene manipulations that promote the conversion of glial cells into retinal neurons, but these cells remain immature, suggesting they lack key factors important to promote full maturation and support functional rescue. In this project, we will expose the fundamental molecular mechanisms underlying glia reprogramming and identify factors that allow full maturation of reprogrammed cells to support retinal repair. Ultimately, this work will uncover the optimal code for endogenous cell reprogramming, offering new therapeutic opportunities for incurable neurodegenerative diseases in the retina that may be extrapolated to other regions of the central nervous system.