79 - Modeling of down Syndrome Pathophysiology in the Retina Using Human Stem Cell-Derived Retinal Organoids

Poster Board Number: 79
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Abstract Body : Introduction/Objective

Down Syndrome (DS), caused by a triplication of human chromosome 21, is linked to numerous ophthalmic disorders as well as to the development of early onset Alzheimer's Disease (AD) histopathology in 100% of individuals​. The retina in people with DS displays an altered phenotype. Studies have reported an increased retinal thickness, mostly due to a developmental increase in the number of retinal ganglion cells, as well as the presence of amyloid-β (Aβ) plaques and abnormally phosphorylated Tau (pTau) proteins,​ which are characteristic of AD. However, the mechanisms behind these presentations are poorly understood​. Here we use human induced pluripotent stem cell (hiPSC) technology to develop the first 3D human retinal organoid model of DS that will enable studies to elucidate these mechanisms.
Methods
Retinal organoids (ROs) were generated from hiPSC lines derived from patients with DS and healthy controls. Collection was done at days 90-100 of differentiation, and organoids were fixed and cryosectioned for further analysis. Quantification of retinal neuronal cell types and markers of AD histopathology in the ROs was performed using immunofluorescence staining, followed by confocal microscopy and image analysis. Protein quantification for AD markers was done by Western Blot
Results
There was no significant difference in the numbers of photoreceptors, amacrine and horizontal cells between ROs derived from DS patients and healthy controls; however, ganglion cell number was significantly higher in DS ROs. Trisomic organoids also displayed significantly higher expression of pTau and Aβ, as seen by immunofluorescence analysis and protein quantification.
Conclusions
We provide evidence that trisomic ROs recapitulate the tissue structure and AD histopathology seen in the DS retina. Thus, ROs can be used as a model for investigation into the mechanisms responsible for the altered retinal phenotype seen in DS.
Significance
This study validates the first human RO model of DS. As such, this model presents an opportunity to elucidate the mechanisms responsible for retinal pathologies seen in people with DS and aid in the development of therapeutic strategies.