Gene therapy breakthrough allows mice to regain sight

Written by Sharon Salt, Editor

In a recent study, which has been published in Nature Communications, researchers have inserted a gene for green opsin into the eyes of blind mice and reported that a month later, these mice were able to navigate around obstacles as easily as mice with no vision problems.
“You would inject this virus into a person’s eye and, a couple months later, they’d be seeing something,” commented Ehud Isacoff (University California Berkeley, CA, USA). “With neurodegenerative diseases of the retina, often all people try to do is halt or slow further degeneration. But something that restores an image in a few months – it is an amazing thing to think about.”

Approximately 170 million people worldwide live with age-related macular degeneration, whilst 1.7 million people worldwide have the most common form of inherited blindness, termed retinitis pigmentosa.

At present, treatment options for patients are limited to an electronic eye implant that is hooked to a video camera and sits on a pair of glasses – an approach that is awkward, invasive and an expensive setup that produces an image on the retina that is equivalent to only a few hundred pixels. With normal, sharp vision, this involves millions of pixels.

Correcting the genetic defect responsible for retinal degeneration is not straightforward, however, as there are more than 250 different genetic mutations responsible for retinitis pigmentosa alone. Approximately 90% of these kill the rod cells in the retina and typically spares other layers of retinal cells including the bipolar and the retinal ganglion cells.

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Within their study, the researchers succeeded in making 90% of ganglion cells light sensitive. They designed a virus targeted to retinal ganglion cells and loaded it with the gene for a light-sensitive receptor, the green cone opsin. Under normal circumstances, this opsin is expressed by only cone photoreceptor cells and makes them sensitive to green–yellow light.

When injected into the eye, the virus carried the gene into the ganglion cells, which are normally insensitive to light, and made them light-sensitive and able to send signals to the brain that were interpreted as sight.

“To the limits that we can test the mice, you can’t tell the optogenetically-treated mice’s behavior from the normal mice without special equipment. It remains to be seen what that translates to in a patient,” explained John Flannery (University of California Berkeley).

Although the researchers were able to deliver the opsin to most of the ganglion cells in the retina of mice, they would need to inject more virus particles to treat humans, as the human eye contains thousands of times more ganglion cells in comparison to the mouse. However, the team at University California Berkeley have indicated that they have developed the means to enhance viral delivery and hope to insert the new light sensor into a similarly high percentage of ganglion cells.

Flannery concluded that: “When everyone says it will never work and that you’re crazy, usually that means you are onto something. Indeed, that something amounts to the first successful restoration of patterned vision using an LCD computer screen, the first to adapt to changes in ambient light and the first to restore natural object vision.”

The investigators hope to raise funds to take the gene therapy into a human trial within 3 years. Similar adeno-associated virus delivery systems have been approved by the US FDA for eye diseases in people with degenerative retinal conditions and who have no medical alternative.

Sources: Berry MH, Holt A, Salari A et al. Restoration of high-sensitivity and adapting vision with a cone opsin. Nat. Comm. doi:10.1038/s41467-019-09124-x (2019) (Epub ahead of print);