Gene Editing as a Potential Therapeutic Solution for Fuchs Endothelial Corneal Dystrophy

Zhu, Angela Y.; Jaskula-Ranga, Vinod; Jun, Albert S.

doi:10.1001/jamaophthalmol.2018.2324

Cited by 11 publications

(5 citation statements)

References 7 publications

(26 reference statements)

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“…In the future, we can expect the number of clinical studies on targeted, nonsurgical treatments of FECD to grow. These may also include additional approaches such as antifibrotic agents or gene editing according to the abovementioned genetic and molecular pathomechanisms (see Sections 7 and 8) (Matthaei et al 2014a,b;Zhu et al 2018a). Early identification of patients who will benefit from targeted therapeutics will play an important role.…”

Section: Nonsurgical and Pharmacological Therapymentioning

confidence: 99%

Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Matthaei

Hribek

Clahsen

et al. 2019

Annu. Rev. Vis. Sci.

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Fuchs endothelial corneal dystrophy (FECD) is a bilateral corneal endothelial disorder and the most common cause of corneal transplantation worldwide. Professor Ernst Fuchs described the first 13 cases of FECD more than 100 years ago. Since then, we have seen far-reaching progress in its diagnosis and treatment. In the field of diagnostics, new technologies enable the development of more accurate classification systems and the more detailed breakdown of the genetic basis of FECD. Laboratory studies help in deciphering the molecular pathomechanisms. The development of minimally invasive surgical techniques leads to a continuous improvement of the postoperative result. This review highlights and discusses clinical, genetic, pathophysiologic, and therapeutic aspects of this common and important corneal disorder.

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Section: Nonsurgical and Pharmacological Therapymentioning

confidence: 99%

Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Matthaei

Hribek

Clahsen

et al. 2019

Annu. Rev. Vis. Sci.

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“…These observations open the possibility of preventing FECD disease onset or progression with molecular therapies early in the disease course before the onset of irreversible loss of endothelial cells, fibrosis, and corneal edema. We and others have proposed therapeutic strategies that target the TCF4 trinucleotide repeat expansion, including the use of gene editing, 12 antisense oligonucleotides, 13 , 14 , 15 duplex RNAs, 16 trinucleotide repeat-targeting catalytically dead Cas9, 17 and small molecules that bind with repeat RNA. 18 …”

mentioning

confidence: 99%

Loss of Corneal Nerves and Corneal Haze in Patients with Fuchs’ Endothelial Corneal Dystrophy with the Transcription Factor 4 Gene Trinucleotide Repeat Expansion

Gillings¹,

Mastro²,

Zhang³

et al. 2023

Ophthalmology Science

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“…Excision of the CTG18.1 repeat expansion from the genomic DNA of FECD endothelial cells using dual CRISPR-Cas9 cleavage has also been proposed as a potential therapy for FECD. 36 Previous studies have demonstrated the feasibility of this approach in excising the causal CTG DNA repeat expansion in DM1 cell lines with CRISPR-Cas9 and a pair of flanking gRNAs followed by repair of the two DSBs with nonhomologous end joining albeit with variable cutting and repair efficiencies. 37 It remains to be seen whether this approach of excision of a pathogenic genomic DNA repeat is feasible in terminally differentiated cells such as corneal endothelium.…”

Section: Discussionmentioning

confidence: 99%

Trinucleotide Repeat-Targeting dCas9 as a Therapeutic Strategy for Fuchs’ Endothelial Corneal Dystrophy

Rong

Gong

Hulleman

et al. 2020

Trans. Vis. Sci. Tech.

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Fuchs' endothelial corneal dystrophy (FECD) is the leading indication for corneal transplantation. Seventy percent of cases are caused by an intronic CTG triplet repeat expansion in the TCF4 gene that results in accumulation of pathogenic expanded CUG repeat RNA (CUG exp) as nuclear foci in corneal endothelium. A catalytically dead Cas9 (dCas9) can serve as an effective guide to target genomic DNA or RNA transcripts. Here, we examined the utility of the clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 system to effectively target and reduce CUG exp. Methods: We delivered dCas9 and repeat-targeting single guide RNA (sgRNA) expression plasmids to patient-derived endothelial cells using lipofection or lentiviral transduction. We used fluorescence in situ hybridization (FISH) and RNA dot-blot hybridization to quantify CUG exp foci and repeat RNA levels, respectively. TCF4 expression levels were assessed using quantitative PCR (qPCR). Results: Using FISH, we found that expression of both dCas9 and a (CAG) n sgRNA complementary to CUG exp are necessary to reduce foci. We observed a reduction in percentage of cells with foci from 59% to 5.6% and number of foci per 100 cells from 73.4 to 7.45 (P < 0.001) in cells stably expressing dCas9-(CAG) n sgRNA but saw no decrease in cells expressing dCas9-(CUG) n sgRNA or nontargeting control sgRNA. In cells with dCas9-(CAG) n sgRNA, we detected a reduction in CUG exp RNA by dot-blot without any reduction in TCF4 mRNA levels using qPCR. Conclusions: Using CRISPR-dCas9 to target the trinucleotide repeat is a promising treatment for FECD contingent on effective in vivo delivery. Translational Relevance: This work advances a gene therapy for a common age-related degenerative disorder.

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Gene Editing as a Potential Therapeutic Solution for Fuchs Endothelial Corneal Dystrophy

Cited by 11 publications

References 7 publications

Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects

Loss of Corneal Nerves and Corneal Haze in Patients with Fuchs’ Endothelial Corneal Dystrophy with the Transcription Factor 4 Gene Trinucleotide Repeat Expansion

Trinucleotide Repeat-Targeting dCas9 as a Therapeutic Strategy for Fuchs’ Endothelial Corneal Dystrophy

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