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AssigneeTaipei Veterans General Hospital
InventorsShih-Hwa CHIOU, Shih-Jen CHEN, De-Kuang HWANG, Yueh CHIEN, Yi-Ping YANG, Shih-Jie CHOU, Tai-Chi LIN
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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 AAV mediated RS1 gene 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.
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.
A multimodal system, comprising high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures.
A disease model, which is a genetically engineered mice Rs1emR209C.
A disease model, which comprises a patient-derived retinal organoids harboring the patient-specific p.R209C mutation.
A method for treating retinal disease in a subject, which comprising administering to the subject an AAV mediated RS1 gene delivery together with a therapeutic agent targeting the endoplasmic reticulum (ER) stress/eIF2 signaling, mTOR pathway, and the regulation of eIF4 and p70S6K pathways, which ultimately improves bipolar cell integrity, postsynaptic transmission, disorganized retinal architecture and electrophysiological responses.
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