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A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models [scRNA-seq: Rd10]

ABSTRACT: To determine the gene expression changes in the retina of 2-month-old Rd10 mice reared in darkness throughout their lifespan, we collected retina samples from Rd10 and WT (C57BL/6J mice) mice, generated single-cell suspensions, and performed scRNA-Seq (10X Genomics). One group of Rd10 mice was treated for 1 month via dietary administration of tamsulosin, metoprolol and bromocriptine drug cocktail.

ORGANISM(S): Mus musculus

PROVIDER: GSE234797 | GEO | 2024/06/06

REPOSITORIES: GEO

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Project description:Diabetic retinopathy (DR), the leading cause of blindness in working-age adults, is thought to be primarily a microvascular complication of diabetes. As a central element of the retinal neurovascular unit, Müller cells, the major macroglia of the retina, are important for maintaining a healthy and functional retina and play a critical role in several pathological events during DR disease progression. Here, we aim to improve our understanding of Müller cell-specific signalling pathways that are altered during DR disease progression in order to develop novel gene therapy strategies that target Müller cells. We used a multi-omics approach on purified Müller cells from 6-month-old control and diabetic db/db mice, including (i) RNA-seq followed by oPOSSUM-3 transcription factor (TF) binding site cluster analysis, (ii) glial chromatin landscape analysis by ATAC-seq, and (iii) Müller cell proteomics by MS/MS mass spectrometry. This led to the identification of the glucocorticoid receptor (GR, gene ID: Nr3c1) most highly expressed in Müller cells. In cells from diabetic mice, GR mRNA and protein expression is significantly reduced and its target gene cluster downregulated in Müller cells. Importantly, GR was identified as a potential master regulator not only by oPOSSUM analysis based on differentially expressed mRNA in Müller cells, but also validated by the ATAC-seq approach. In an in vitro cortisol-stimulated retinal explant model cortisol not only increased GR phosphorylation, but also induced changes in the expression of known downstream GR target genes. Finally, we evaluated whether AAV-mediated GR overexpression in Müller cells improves retinal functionality and we found moderate improvements indicated by electroretinography. While synthetic and topical glucocorticoids are widely used in ophthalmology with undeniable beneficial effects, our study provides valuable new insight into the role of GR signalling and glial alterations in the diabetic retina. This supports the therapeutic concept of locally enhancing the GR signaling axis. Our findings of reduced GR levels in Müller cells of the diabetic retina suggests that therapeutic approaches should aim at increasing the expression of the receptor rather than adding more ligand.

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A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models [scRNA-seq: Rd10]

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