Gene-Editing Gains Momentum for Saving Vision

February 02, 2016

Researchers at Cedars-Sinai Medical Center in Los Angeles used an innovative gene-editing technique to prevent vision loss in a rodent model of autosomal dominant retinitis pigmentosa (adRP). The emerging therapy specifically shuts down the S334ter-3 mutation in the gene rhodopsin (RHO), a common cause of adRP.                       

The success of the study is a significant step forward in developing a gene-editing therapy for saving and restoring vision for people affected by adRP as well as other inherited retinal diseases. Results of the study were published in the journal Molecular Therapy.

The gene-editing technique used by the Cedars-Sinai team is called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9. Unlike gene-replacement therapies—many of which are in human studies for retinal diseases and involve delivery of an entire new, healthy gene—CRISPR/Cas9 corrects only the defect in the recipient’s mutated gene.

The CRISPR/Cas9 approach repurposes the naturally occurring defense system that bacteria use to find and disable invading viruses. In gene editing, CRISPR locates the target—i.e., the mutated gene—and Cas9 snips out the mutation.

In this adRP study, the genetically engineered rodent has normal and mutated copies of RHO. The Cedars-Sinai treatment shut down the mutated copies, leaving the normal copies of RHO intact, thereby expressing normal RHO protein to provide vision.

One major advantage of CRISPR/Cas9 is it gets around the problem of delivering large genes linked to retinal diseases—CEP290 or USH2A, for example—that won’t fit in the viral delivery systems designed to carry them into retinal cells.

Also, CRISPR may be a simpler approach to treating diseases in which delivering a whole new gene is not necessary; simply shutting down or repairing the bad gene may be enough to save vision. This is often the case in adRP.

Shaomei Wang, M.D., Ph.D., the principal investigator for the Cedars-Sinai study, is cautiously optimistic about the potential of this emerging approach to gene correction. “Additional research is needed to show the feasibility of delivering the treatment at different stages of disease and demonstrating long-term safety and efficacy,” she says. “But with rapid development of this powerful technology, CRISPR/Cas9-based therapies will likely be used in clinical trials in the foreseeable future.”

The gene-editing company Editas is currently developing a therapy to correct mutations in the gene CEP290, which can cause retinitis pigmentosa and Leber congenital amaurosis.

Don Zack, M.D., Ph.D., at Johns Hopkins University, is being supported by the Foundation to develop a CRISPR/Cas9 therapy for adRP caused by P23H mutations in the RHO gene and optimize the delivery of the CRISPR/Cas9.

“CRISPR/Cas9 was one of the hottest topics at the ARVO ophthalmology research conference last May,” says Stephen Rose, Ph.D., Foundation Fighting Blindness. “While it is still a relatively new area of research, it is developing quickly, and we are excited about its potential for treating inherited retinal degenerations and, as such, to be investing in it.”