CRISPR-Cas9 Treatment for Fuchs' Corneal Dystrophy

Article: Knight Campus researchers develop gene therapy for eye disease
Source: University of Oregon, via NEI
Published: [August 3, 2021]
Article: Scientists use CRISPR-Cas9 to prevent Fuchs' corneal dystrophy in mice
Source: Medical Xpress  and EurekAlert
Published: August 3, 2021

Ad-Cas9-Col8a2gRNA intracameral injection
rescues corneal endothelium loss in
early-onset Fuchs’ dystrophy in mice

Fuchs' endothelial corneal dystrophy (FECD) is the leading cause of corneal transplant in the U.S. and although there is no shortage of donor corneal tissue in this country, corneal transplant is surgery that comes with many risks. Even a successful surgery that restores clear vision with a donor cornea commits the patient to many office visits, co-pays, and post-operative eye drops. A treatment that could be administered prior to or in place of surgery could therefore provide patients with additional options and benefits. As part of an eight-year study, a team of researchers is exploring the use of CRISPR-Cas9 gene editing to knockdown the expression of a mutant protein responsible for a form of Fuchs' endothelial corneal dystrophy. In particular, they are focusing on a single-point mutation in a collagen protein known as COL8A2, or collagen type VIII alpha 2 chain, which causes an early-onset subset of the disease that typically affects patients in their late 30s or early 40s. Notably, previous research in mice showed that silencing the COL8A2  gene did not adversely affect the cornea; rather, it is the mutant variant, a missense mutation, of the protein that causes problems.

The researchers developed a new technique, called start codon disruption, in which they disrupt the initiation site of transcription, the start codon, thereby preventing protein synthesis. While other techniques that disrupt gene expression farther down the gene can also result in termination of protein expression, the farther downstream along the gene, the more likely a viable protein would still be produced that instead has unknown, and possibly unwanted, activity. This research is also novel in the sense that it applies CRISPR gene editing to post-mitotic cells, in this case the corneal endothelium, the cells of which are not replenished as a person ages. Significant loss of corneal endothelial cells leads to loss of pumping function, and in this case results in corneal edema leading to impaired vision. The treatment has so far been tested in mice by intracameral delivery of the gene therapy via adenovirus viral vector. The team reports both preservation of endothelial cells as well as rescue of endothelium pump function with no adverse effects to the surrounding tissues and a safe drug profile for the retina, iris, and other parts of the eye at the maximum tolerated dose. The researchers will continue studies in small animals and non-human primates before moving on to clinical trials. However, the study's senior researcher is hopeful that the therapy will one day reduce the need for corneal transplants for Fuchs’ dystrophy patients, thereby both directly benefiting those patients as well as indirectly helping other patients in need of corneal tissue.

My rating of this study: ⭐⭐⭐

Uehara H, Zhang X, Pereira F, et al. "Start codon disruption with CRISPR/Cas9 prevents murine Fuchs’ endothelial corneal dystrophy." eLife.  10:e55637. 8 June 2021. https://doi.org/10.7554/eLife.55637