Targeting retinal degeneration: Pharmacological approaches in rp, ipscderived retinal organoids and molecular biomarkers in amd

• Autores: Seyed MohamadMehdi Moshtaghion
• Directores de la Tesis: Estefanía Caballano Infantes (dir. tes.), Francisco Javier Díaz Corrales (dir. tes.)
• Lectura: En la Universidad de Sevilla ( España ) en 2026
• Idioma: inglés
• Número de páginas: 185
• Enlaces
  • Tesis en acceso abierto en: Idus
• Resumen

  • Retinal degenerative diseases (RDDs), including Retinitis Pigmentosa (RP, a genetic disorder causing progressive vision loss) and Age-related Macular Degeneration (AMD, a condition resulting in central vision deterioration), are leading causes of irreversible blindness worldwide. Despite advances in molecular genetics, and stem cell biology, effective treatments remain limited due to extensive genetic heterogeneity and the complex pathophysiology of these disorders. This doctoral thesis is structured into two main chapters and combines pharmacological, cellular, and molecular strategies to elucidate key degenerative mechanisms and identify potential therapeutic targets in RP, while exploring molecular biomarkers for AMD. By bridging basic research with translational ophthalmology, this work aims to contribute to the development of novel therapeutic approaches and to the validation of a new biomarker as a potential tool for monitoring disease progression in leading RDDs.

    The first charter investigated parthanatos, a type of programmed cell death caused by overactivation of the enzyme PARP1, as a central mechanism of photoreceptor cell death in RP. Piceid octanoate (PIC-OCT), a novel bioactive resveratrol derivative, showed potent retinoprotective effects in both in vitro (661W photoreceptor cells) and in vivo (rd10 mice) RP models. PIC-OCT modulated the SIRT1/PARP1 signaling axis (a pathway that regulates cell survival), reduced oxidative stress, preserved mitochondrial integrity, and delayed photoreceptor degeneration. These findings identify PIC-OCT as a promising mutation-independent neuroprotective agent. It mitigates oxidative DNA damage and metabolic dysfunction, providing a potential pharmacological complement to gene therapy in RP.

    In addition, the second phase of this first charter focused on developing human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) as a translational in vitro model.

    This model is used for studying DNA damage–associated degeneration and testing therapeutic compounds. ROs were generated from both wild-type (WT) and disease-specific (NMNAT1-V9M) hiPSC lines. They reproduced key structural and molecular features of early human retinogenesis in normal and pathological conditions. These organoids offer a physiologically relevant human platform for modeling inherited retinal dystrophies, investigating parthanatos-related mechanisms, and testing new retinoprotective strategies.

    The second charter component addressed AMD with the study and validation of a new biomarker. This study integrated preclinical and clinical data. Using a laser-induced choroidal neovascularization (LCNV) mouse model, a method to mimic abnormal blood vessel growth in the eye, dynamic vascular endothelial growth factor (VEGF) changes were analyzed in relation to blood vessel formation (angiogenic pathways) and inflammation. Clinical validation in AMD patients showed VEGF levels in tears closely reflect VEGF activity inside the eye and match disease severity. This makes tears a non-invasive, repeatable source of diagnostic and prognostic markers. Additionally, our results showed sex-related differences in VEGF expression, which may have important implications for the design of personalized anti-VEGF therapies.

    This thesis advances the understanding of the molecular and cellular mechanisms driving retinal degeneration—from oxidative DNA damage and parthanatos-mediated cell death to biomarker identification. The integrative approach—combining neuropharmacology, stem cell–based modeling, and translational diagnostics—highlights novel therapeutic and diagnostic avenues to mitigate retinal blindness and lays the foundation for future precision medicine interventions in RDDs.