Opsins make ‘blind’ cells light-sensitive; potential human treatment within three years — ScienceDaily


This is simply too simple. Scientists at the University of California, Berkeley, inserted a green-light receptor gene into the eyes of blind people. A month later, they sailed around obstacles like mice without vision problems. They can see the movement on the iPad, the brightness changes over a thousand times the range and details, enough to distinguish the letters.

The researchers say that in just three years, gene therapy – transmitted by inactivated viruses – can be tested in humans blinded by retinal degeneration, ideally giving them enough vision to move and possibly resume reading. Or the ability to watch videos.

"You will inject this virus into one's eyes. After a few months, they will see something," said Berkeley and Professor of Cell Biology at the University of California, Heilongjiang Institute of Neuroscience. Ehud Isakov said. "For neurodegenerative diseases of the retina, usually everyone tries to stop or slow down further degradation. But recovering the image in a few months – this is a surprising thing."

About 170 million people worldwide have age-related macular degeneration, including one-tenth of those over the age of 55, and 1.7 million people worldwide suffer from the most common hereditary blindness – the retina Pigmentation, which usually blinds people to 40 years old.

"I have friends who have a sense of light, and their lifestyle is heartbreaking," said John Flannery, a professor of cell biology at the University of California at Berkeley, who is a member of the School of Optometry. “They have to think about the people they take for granted. For example, every time they go to the hotel, the layout of each room is different. They need someone to make a 3D map in their mind while walking around the room, such as low. A short coffee table may be a danger of corruption. The burden of suffering from severe, disabling vision loss is enormous, and they may be the first candidates for this treatment."

Currently, the choice of such patients is limited to electronic eye implants connected to cameras sitting on a pair of glasses – a clumsy, invasive and expensive setting that produces the equivalent of the current image on the retina, to A few hundred pixels. Normal, sharp vision involves millions of pixels.

Correcting genetic defects that cause retinal degeneration is also not straightforward, as only 250 different genetic mutations cause retinitis pigmentosa. About 90% of them will kill the photoreceptor cells of the retina – rods and cones that are sensitive to dim light for daylight color perception. However, retinal degeneration often leaves other layers of retinal cells unaffected, including bipolar and retinal ganglion cells, which remain healthy for decades after they are completely blind, although they are not sensitive to light.

In their mouse trial, the University of California, Berkeley team succeeded in making 90% of ganglion cells sensitive to light.

Isacoff, a colleague of Flannery and his UC Berkeley, will report their success in an article published on March 15th at Nature Communications .

'You could have done this 20 years ago'

To reverse the blindness of these mice, the researchers designed a virus that targets retinal ganglion cells and loaded them into the light-sensitive receptor gene, a green (medium-wavelength) cone-like opsin. Typically, the opsin is expressed only by cone photoreceptor cells and is made sensitive to greenish yellow light. When injected into the eye, the virus carries the genes into ganglion cells that are generally insensitive to light and makes them sensitive to light and can send signals to the brain that are interpreted as visual.

"For the limits we can test mice, you can't tell optogenetic mice to behave from normal mice without special equipment," Flannery said. "There is still a shift in the patient to be observed."

In mice, researchers are able to deliver opsin to most of the ganglion cells in the retina. In order to treat humans, they need to inject more viral particles because the human eye contains thousands of times more ganglion cells than the mouse eye. But the team at the University of California, Berkeley, has developed ways to enhance viral delivery and hopes to insert new light sensors into the same high percentage of ganglion cells, which is equivalent to the very high number of pixels in the camera.

After more than a decade of trying more complex programs, Isacoff and Flannery discovered simple solutions, including the surviving combination of retinal cells inserted into genetically engineered neurotransmitter receptors and photochemical switches. These work, but did not reach the sensitivity of normal vision. Opsins from microbes tested elsewhere have lower sensitivity and require the use of optical magnification goggles.

In order to capture the high sensitivity of natural vision, Isacoff and Flannery turn to photoreceptor opsins of photoreceptor cells. Using adeno-associated virus (AAV), a naturally infected ganglion cell, Flannery and Isacoff successfully delivered the gene of retinal opsin into the genome of ganglion cells. Previously blind mice gained vision for a lifetime.

"This system is really very satisfying, in part because it is also very simple," Isacoff said. “The irony is that you can do this 20 years ago.”

Isacoff and Flannery are raising funds to incorporate gene therapy into human trials within three years. A similar AAV delivery system has been approved by the FDA for eye disease in people with degenerative retinal disorders and without medical substitutes.

It does not work properly

According to Flannery and Isacoff, most people in the field of vision suspect that opsin can function outside of their specialized rod and cone photoreceptor cells. The surface of the photoreceptor is decorated with opsin – rhodopsin in the rod and red, green and blue opsin in the cone – embedded in a complex molecular machine. Molecular relay–G protein coupled receptor signal cascade – effectively amplifies the signal, enabling us to detect a single photon. Once the enzyme detects photons and becomes "bleached," the enzyme system recharges the opsin. Feedback adjustment adapts the system to different background brightness. And the dedicated ion channel produces an effective voltage signal. If the entire system is not ported, it is reasonable to suspect that the operation does not work.

But Isacoff specializes in G-protein coupled receptors in the nervous system, and he knows that many of these parts are present in all cells. He suspects that opsin is automatically linked to the signaling system of retinal ganglion cells. He and Flannery first tried rhodopsin, which is more sensitive than light-looking proteins.

To their delight, when rhodopsin was introduced into the ganglion cells of mice, the rods and cones of these mice were completely degraded, and thus blinded, and these animals regained recognition from the light. The ability of darkness – even weak indoor light. However, the rhodopsin results were too slow and failed in both image and object recognition.

Then they tried green cone opsin, which responded 10 times faster than rhodopsin. It is worth noting that these mice are able to distinguish between parallel and horizontal lines, with long distances between lines (standard human visual acuity tasks), moving lines and stationary lines. The restored field of view is very sensitive and the iPad can be used for visual display instead of brighter LEDs.

"This powerfully takes the information home," Isakov said. “After all, the blind people regained the ability to read standard computer monitors, communicate through video, and watch movies.”

These successes have made Isacoff and Flannery want to go further and find out if animals can sail in a world of vision recovery. What is striking is that the green cone vision is also successful. Blind mice regain the ability to perform their most natural behavior: identifying and exploring three-dimensional objects.

Then they asked a question, "What if the visually restored person enters the brighter light outdoors? Are they blinded by the light?" Here, another prominent feature of the system appears, Isacoff said. : Green cone retinal signaling pathway adaptation. Animals that previously blindly adapted to changes in brightness can perform tasks as if they were animals. This adaptive work is in the range of about a thousand times – the difference is the difference between average indoor and outdoor lighting.

"When everyone says it will never work and you are crazy, usually that means you will make a difference," Flannery said. In fact, this is equivalent to the first successful restoration of pattern vision using an LCD computer screen, the first to adapt to changes in ambient light, the first to restore the vision of natural objects.

The team at the University of California at Berkeley is now testing themes that can restore color vision and further improve acumen and adaptability.

This work was supported by the National Institute of Ophthalmology of the National Institutes of Health, the Center for Biofunctional Optical Control Nanomedicine, the Blindness Foundation, the Vision Foundation and the Loy Medical Institute.


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