Glaucoma gene therapy on positive trajectory using CRISPR-Cas9

Seattle-Results from a series of preclinical studies are providing proof of principle that gene targeting using CRISPR-Cas9 genome-editing technology can prevent or treat glaucoma associated with mutations in the myocilin (MYOC) gene, said Val Sheffield, MD, PhD.

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Speaking at ARVO 2016, Dr. Sheffield, professor of ophthalmology and visual sciences, University of Iowa Carver College of Medicine Iowa City, reviewed findings from a research project that has its roots more than 25 years ago.

It began with determination that mutations in myocilin coded for by the MYOC gene were the cause for an autosomal dominant early onset form of open-angle glaucoma. Next it was determined that the pathophysiology involved protein misfolding leading to endoplasmic reticulum stress in the trabecular meshwork and subsequently elevated IOP.

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Discussing the research focusing on gene therapy using the CRISPR-Cas9 system, Dr. Sheffield said the strategy is to create insertions or deletions resulting in frameshift mutations leading to stop mutations.

The first studies were done in vitro using mouse trabecular meshwork cells and human primary trabecular meshwork cells. In the next phase, the research advanced into in vivo studies, first using the ashMYOCY437H transgenic animal.

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Treatment of 1-month old mice, which had not yet developed elevated IOP, using Ad-5-CRISPR-Cas9 virus with guide RNAs targeting exon 1 of the MYOC gene was shown to relieve endoplasmic reticulum stress in the trabecular meshwork cells and mitigate elevations in IOP that occurred in animals treated with CRISPR-Cas9 with control guide RNA.