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Crispr Deployed to Correct Inherited Vision Disorder

Editing DNA

(LaCasadeGoethe, Pixabay)

11 May 2018. Researchers at Columbia University developed and tested in lab mice a technique using the genome editing technology Crispr with gene replacement therapy to correct the inherited eye disease retinitis pigmentosa. The technique and test results are described in yesterday’s issue of the journal Ophthalmology (paid subscription required), published by American Academy of Ophthalmology.

The team led by Stephen Tsang, professor of ophthalmology, cell biology, and pathology at Columbia’s medical school, is seeking a more reliable genetic therapy for retinitis pigmentosa, a disorder affecting the retinas in some 100,000 people in the U.S., or about 1 in 2,700 individuals. The retina is a layer on the back of the eye with light-sensitive cells that convert light into neural signals, carried into the brain by the optic nerve. Retinitis pigmentosa is an eye disease caused by genetic defects that damages cells in the retina affecting night vision, and sometimes peripheral and central vision, leading to blindness.

Crispr — short for clustered regularly interspaced short palindromic repeats — is receiving more attention as a potential therapeutic technique. It’s a genome-editing process based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr employs enzymes that cleave DNA strands at the desired points, with Crispr-associated protein 9, or Cas9, being the enzyme used for the longest period.

To treat retinitis pigmentosa, however, Tsang and colleagues discovered Crispr needs careful targeting and by itself is not sufficient. The disease results in about 30 percent of cases from a defect in the RHO gene that gives instructions for the protein rhodopsin needed for proper functioning of light receptor cells in the retina providing vision in low light. Plus, retinitis pigmentosa is an autosomal dominant disorder, where one only mutated copy of the gene from parents in each cell is needed to cause the disease. As a result, Crispr editing needs to cut out the mutated copy of the RHO gene, but leave the healthy copy intact.

The meet this requirement, the researchers deployed a strategy with 2 RNA molecules guiding the Crispr editing process. The editing enzymes are delivered with adeno-associated virusesbenign, naturally occurring microbes that can infect cells, but do not integrate with the cell’s genome or cause disease, and may generate a mild immune response. In this process, RNA also guides the viruses to deliver a healthy RHO gene to the retinas.

The team tested the process they call ablate-and-replace in lab mice bred with defective RHO genes. Tests of eyes in the mice used  electroretinography that measures electrical responses of light-sensitive cells in the retina. The results show more retinal cells in mice receiving the full ablate-and-replace treatments were functioning than comparable mice receiving gene therapy alone. Moreover, after 3 months following treatment, the outer layers of retinas in mice receiving ablate-and-replace therapy were 17 to 36 percent thicker than mice receiving only gene therapy.

While the Columbia researchers designed the tests to prove the ablate-and-replace concept for retinitis pigmentosa, they believe the strategy can be applied to other autosomal dominant disorders in in ophthalmology and other fields. Tsang tells American Academy of Ophthalmology clinical trials of the technique could begin in 3 years.

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