Identifying Multiomic Signatures of X-Linked Retinoschisis-Derived Retinal Organoids and Mice Harboring...

Area of Science:

• Genomics and Molecular Biology
• Ophthalmology
• Cell Biology

Background:

• X-linked retinoschisis (XLRS) is an inherited retinal disorder causing severe vision loss.
• Understanding XLRS pathomechanisms requires dissecting complex transcriptional networks and cell interactions.
• Multiomics approaches, integrating single-cell RNA sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST), offer powerful tools for this investigation.

Purpose of the Study:

• To elucidate XLRS-specific transcriptomic signatures using a multimodal approach.
• To identify conserved disease pathways and validate molecular mechanisms in XLRS models.
• To evaluate therapeutic strategies targeting identified pathways for XLRS.

Main Methods:

• High-throughput scRNA-seq and ST were employed on genetically engineered mice and patient-derived retinal organoids.
• Multiomics transcriptomic analysis identified key signaling pathways involved in XLRS.
• Western blots, proteomics, and AAV-mediated gene delivery were used for validation and therapeutic assessment.

Main Results:

• Chronic endoplasmic reticulum (ER) stress/eukaryotic initiation factor 2 (eIF2) signaling, mTOR, eIF4, and p70S6K pathways were identified as conserved in XLRS models.
• Validation confirmed unfolded protein responses, chronic eIF2α signaling, and ER stress-induced apoptosis.
• Therapeutic targeting of ER stress/eIF2α synergistically enhanced RS1 gene therapy, improving retinal integrity and function.

Conclusions:

• The multiomics approach successfully identified conserved disease pathways in XLRS.
• Targeting ER stress/eIF2α signaling presents a promising therapeutic strategy for XLRS.
• This study provides a foundation for developing novel treatments for XLRS and other inherited retinal diseases.