Novel stem cell-based retinal transplant and swine model of retina degeneration: enabling technologies for regenerative therapies

• Autores: Silvia Aparicio Domingo
• Directores de la Tesis: Nicolás Cuenca Navarro (dir. tes.), M. Valeria Cantó Soler (codir. tes.)
• Lectura: En la Universitat d'Alacant / Universidad de Alicante ( España ) en 2023
• Idioma: inglés
• Número de páginas: 190
• Tribunal Calificador de la Tesis: Pedro Lax Zapata (presid.), Francisco Javier Sancho Pelluz (secret.), Laura Campello Blasco (voc.)
• Programa de doctorado: Programa de Doctorado en Biología Experimental y Aplicada por la Universidad de Alicante
• Enlaces
  • Tesis en acceso abierto en: RUA
• Resumen

  • Background. Age-related Macular Degeneration (AMD) is the leading cause of irreversible visual impairment in the elderly. The quality of life for our patients depends upon developing novel therapies that reverse vision loss. AMD is a degenerative condition of the photoreceptors, the cells in the retina that respond to light, and the pigmented epithelial cells (RPE) that support their function. Existing cell therapy strategies replacing RPE or photoreceptors independently may not completely rescue the remaining compromised cells. Here, we sought to develop a novel cell-based approach to regenerate photoreceptors and RPE cells together. Due to the limitations of available animal models mimicking AMD, we aimed to develop a pre-clinical animal model that recreates key aspects of AMD and validate our cell therapy approach. Methods. Human retinal organoids with physiologically competent photoreceptors and functionally mature polarized human RPE monolayer derived from stem cells were generated to develop a novel three-dimensional neural retina (NR)/RPE transplant for cell therapy. We used Yucatan swine to establish a novel AMD pre-clinical model by selectively injuring the retina applying the most sophisticated laser technology and, to test the feasibility of our cell-based therapy further. Animals were longitudinally studied by indirect ophthalmoscope evaluation (i.e., fundus camera imaging, SD-OCT, ICGA, and FA). Results. We have established a novel 3DNR/RPE complex that recreates the cellular composition and organization of the native outer retina, including the physical and functional association between the RPE and photoreceptor cells. Furthermore, we established proof-of-concept on the feasibility of transplanting our 3DNR/RPE complex in a pre-clinical swine model of retinal degeneration. We demonstrated atraumatic deployment of the 3DNR/RPE complex at the target location and survival of the implant. Conclusions. The studies provide a comprehensive set of data enabling technologies for pre-clinical and clinical phases of stem cell-derived regenerative therapies that could be applied to clinical trials for advanced AMD, including patients with Geographic Atrophy.