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Gene therapy for glaucoma using a combination targeting multiple genes with CRISPR-CasRx

ABSTRACT: Gene therapy for glaucoma using a combination targeting multiple genes with CRISPR-CasRx

PROVIDER: PRJNA1040300 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26830463_1.fastq.gz	Fastqsanger.gz
	SRR26830463_2.fastq.gz	Fastqsanger.gz
	SRR26830464_1.fastq.gz	Fastqsanger.gz
	SRR26830464_2.fastq.gz	Fastqsanger.gz
	SRR26830465_1.fastq.gz	Fastqsanger.gz

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Gene therapy for glaucoma using a combination targeting multiple genes with CRISPR-CasRx

Project description:Glaucoma affects approximately 80 million individuals worldwide, a condition for which current treatment options are inadequate. The primary risk factor for glaucoma is elevated intraocular pressure, which is currently the only controllable treatment approach. Elevated intraocular pressure is determined by the balance between the secretion and outflow of aqueous humor (AH). Utilizing CRISPR Cas9 to disrupt the expression of the AQP1 protein, which decreases the ciliary AH secretion, resulted in an approximate 22% reduction in intraocular pressure. Nevertheless, the effectiveness of single-gene therapies is limited. To address this limitation, we conducted experiments using two mouse models of ocular hypertension. Our findings indicate that reducing the expression of the genes Rock1 and Rock2, which are associated with the outflow of AH at the trabecular meshwork (TM), as well as the genes Aqp1 and Adrb2, which are related to the generation of AH at the ciliary body (CB), can significantly reduce intraocular pressure and provide protection to the retina ganglion cells (RGCs), ultimately delaying disease progression. In addition, we elucidated the mechanisms by which the knockdown of Rock1 and Rock2, or Aqp1 and Adrb2, reduces the IOP and secures RGCs by single-cell sequencing.

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Project description:The pathogenesis of glaucoma is strongly associated with the occurrence of autoimmune-mediated loss of retinal ganglion cells (RGCs) and recently it was proven that specific antibody-derived signature peptides are significantly differentially expressed in sera of primary open angle glaucoma patients (POAG) compared to healthy controls. Synthetic antibody-derived peptides are known since several years to modulate various effector functions of the immune system and to act as antimicrobial or antiviral molecules. The present study shows for the first time that polyclonal-derived complementarity-determining regions (CDRs) significantly increased the survival rate of RGCs in an ex vivo glaucoma model (P=0.013) by using immunohistochemical staining techniques. Affinity capture experiments verified serine protease HTRA2 (mitochondrial) as high-confident retinal epitope target of CDR1 sequence motive ASGYTFTNYGLSWVR. Quantitative proteomic analysis of the CDR-treated retinal explants revealed increased expression of various anti-apoptotic and anti-oxidative proteins (e.g. VDAC2 and TXN) compared to untreated controls (P<0.05) and decreased expression levels of cellular stress response markers (e.g. HSPE1 and HSP90AA1) were observed. Mitochondrial dysfunction, protein ubiquitination pathway and oxidative phosphorylation were annotated as the most significantly affected signaling pathways and can possibly be traced back to the CDR-induced inhibition or modulation of the master regulator HTRA2. These findings emphasize the great potential of synthetic polyclonal-derived CDR peptides as therapeutic agents in future glaucoma therapy and provide an excellent basis for affinity-based biomarker discovery purposes.

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