Cell replacement to improve sight: Human rod photoreceptor transplantation into mouse models of retinitis pigmentosa

• Applicants: Professor Dr. Marius Ader; Dr. Andreas Dahl
• Subject Area: Ophthalmology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568096511

Loss of the light-sensing photoreceptors in the retina causes vision impairment and blindness with currently no therapies clinically established. Two principal types of photoreceptors are found in the mammalian (human) retina: rods and cones. While rods provide vision in dim light conditions, cones are responsible for day-light, color, and high-acuity vision. Retinal degenerative diseases are characterized by high heterogeneity including inherited forms with disease-causing mutations identified in more than 260 genes. Transplantation of pluripotent stem cell- (PSC) derived photoreceptors represents a potential general treatment approach. Indeed, our recent pre-clinical studies provide evidence for extensive integration and maturation of transplanted induced (i) PSC-derived cone photoreceptors, resulting in improved light responses in a cone degeneration mouse model. However, many cases of retinal degeneration are characterized by primarily rod photoreceptor loss followed by secondary cone death. Therefore, this study aims to assess the use of iPSC-derived rod photoreceptors for transplantation into multiple disease conditions provided by three different mouse models, that recapitulate the wide range of pathologies of patients suffering from retinitis pigmentosa. The integration, maturation, and functional potential of human donor rods will be assessed at multiple levels by histological, cellular, molecular, electrophysiological, and behavioral assays to decipher the mechanism of rod replacement and additional protection of endogenous cones. Results will therefore be of utmost importance in the development of reliable parameters as a fundament for the translation of photoreceptor replacement approaches towards clinical application.

• DFG Programme: Research Grants