Method for treating x-linked retinoschisis

Abstract

The present invention provides a multiomics approach, which integrate single-cell RNA-sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell-cell interactions involved in biomolecular pathomechanisms. The present invention also provides a multimodal approach combining high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures in two XLRS-like models with retinal splitting phenotypes, including genetically engineered (Rs1emR209C) mice and patient-derived retinal organoids harboring the same patient-specific p.R209C mutation. Through multiomics transcriptomic analysis, the endoplasmic reticulum (ER) stress / eIF2 signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways as chronically enriched and highly conserved disease pathways between two XLRS-like models are identified. Western blots and proteomics analysis validated the occurrence of unfolded protein responses, chronic eIF2α signaling activation, and chronic ER stress-induced apoptosis. Furthermore, therapeutic targeting of the chronic ER stress / eIF2α pathway activation synergistically enhanced the efficacy of AAVmediated RS1gene delivery, ultimately improving bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture and electrophysiological responses. Collectively, the complex transcriptomic signatures obtained from Rs1emR209C mice and patient-derived retinal organoids using the multiomics approach provide opportunities to unravel potential therapeutic targets for incurable retinal diseases, such as XLRS.

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