New Frontier in the Management of Corneal Dystrophies: Basics, Development, and Challenges in Corneal Gene Therapy and Gene Editing

Abstract

: Corneal dystrophies represent a group of heterogeneous hereditary disorders causing progressive corneal opacification and blindness. Current corneal transplant management for corneal dystrophies faces the challenges of repeated treatments, complex surgical procedures, shortage of appropriate donor cornea, and, more importantly, graft rejection. Genetic medicine could be an alternative treatment regime to overcome such challenges. Cornea carries promising scope for a gene-based therapy involving gene supplementation, gene silencing, and gene editing in both ex vivo and in vivo platforms. In the cornea, ex vivo gene therapeutic strategies were attempted for corneal graft survival, and in vivo gene augmentation therapies aimed to prevent herpes stromal keratitis, neovascularization, corneal clouding, and wound healing. However, none of these studies followed a clinical trial–based successful outcome. CRISPR/Cas system offers a broad scope of gene editing and engineering to correct underlying genetic causes in corneal dystrophies. Corneal tissue--specific gene correction in vitro with minimal off-target effects and optimal gene correction efficiency followed by their successful surgical implantation, or in vivo CRISPR administration targeting pathogenic genes finds a way to explore therapeutic intervention for corneal dystrophies. However, there are many limitations associated with such CRISPR-based corneal treatment management. This review will look into the development of corneal gene therapy and CRISPR-based study in corneal dystrophies, associated challenges, potential approaches, and future directions.

Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy

“…The SLC4A11 mutational spectrum can help to develop medicinal approaches and regenerative medicine, such as Gene Therapy (GT) or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based gene editing, [14][15][16]. Also showed in our recent publication on corneal [17]. Screening for familial CHED cases also helps to measure the risk and manage the disease.…”

Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis

“…There are also genetic dimorphisms that impact corneal health. Many corneal dystrophies are manifested through single nucleotide polymorphisms (SNPs) in growth factor genes like TGF-β [139] and HGF [140] (though this has only been seen in certain demographics and not others [141,142]).…”

Ocular Gene Therapy: Literature Review

“…Based on the enzyme defect and ailment severity, seven one of a kind types of MPS have been diagnosed [272,273]. Administration of Ad expressing human β-glucuronidase gene, which is mutated in MPS-VII, into the anterior chamber or intrastromal vicinity of the affected mouse corneas correctly handled corneal clouding in MPS-VII [274]. A comparable impact was once additionally considered in a mannequin of canines MPS VII [275].…”