ReDiMoAMD: Human organoid system based therapy discovery and development for age-related macular degeneration
Description: Age-related macular degeneration (AMD) causes vision loss due to photoreceptor (PR) degeneration, but disease models and therapies are missing. PR transplantation represents a promising treatment approach, but clinical translation has up to now not been achieved. Our consortium aims to bridge two related research gaps: modeling of AMD pathology and therapy development (preventive and restorative). We developed an induced pluripotent stem cell (iPSC)-based human retinal organoid (HRO) model with complex cellular and molecular AMD hallmarks: Combined application of two proinflammatory factors, previously associated with AMD risk and pathology and produced by microglia, dying neurons, and reactive glia, induce cone and rod PR dystrophy and several glial pathologies, including gliosis, remodeling and scar formation, that, similar to AMD lesions, develop simultaneously. Notably, PR dystrophy occurs via cell extrusion, a pathology also described in many AMD patients and in ageing. Thus, this technology represents the first system for studying human-to-human transplantation in addition to preclinical animal work. PR extrusion mechanisms might offer targets to prevent AMD and to improve PR transplantation – since both might share common and/or interrelated processes. For example, metabolic stress and inflammation, which are key in AMD and known triggers of cell extrusion in other organs, might cause PR extrusion. Furthermore, we hypothesize that mech¬anisms regulating PR extrusion might facilitate PR transplant integration (reverse extrusion hypothesis). Indeed, our preliminary results show that human PR transplants placed onto the human PR extrusion pathology model integrate in large numbers. Thus, our aims are: (A) Decipher pathomechanisms by comparing the AMD-like model in HROs and mice. (B) Introduce and determine the function of microglia in the HRO pathology model. Microglia mediated inflammation might be key in AMD and microglia might cause or respond to PR extrusion. (C) Assess pathologic changes of PR and glia by metabolomics and lipidomics, since an increase in glycolysis might cause PR extrusion and glial scar formation; additionally, study its interrelationships with microglia as a potential inducer of glycolysis in the retina. (D) Utilizing our mechanistic findings, we aim to prevent pathogenesis and optimize PR trans¬¬plantation into our AMD-like HRO and mouse models. To achieve this, we will: Develop and apply a platform for human PR transplantation into HROs; apply and establish human PR and glia specific targeting by adeno-associated virus (AAVs) for basic research and therapy, respectively; identify potential regulators of AMD pathologies; and modify potential targets that might induce PR extrusion to prevent pathogenesis or stimulate PR transplant integration. In summary, the establishment of AMD-related preclinical human models to study pathomechanisms and therapy approaches represents an essential fundament to pursue towards clinical translation.
Amount: CHF 274,700
Funding type: research
Funder scheme: ERA-NET NEURON
Start date: 2022-01-01
End date: 2024-12-31
Investigator: Zamboni, Nicola
Institution: ETH Zurich – ETHZ
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: 197785
OpenAlex ID: G7788346632