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Gene therapy sensitises retinas to near-infrared light

A new strategy for reversing vision loss from macular degeneration

In a step towards reversing vision loss caused by macular degeneration, researchers have for the first time sensitized blind retinas to near-infrared light. The achievement is published in Science.

Macular degeneration affects nearly 200 million people globally, most of them over the age of 60. It results from deterioration of the macula, which is a small light-sensitive structure at the back of eye. Patients retain their peripheral eyesight, but lose central vision over time.  And though treatments can delay progression, the disease currently has no cure.

"By enabling near-infrared light sensitivity, we hope to ultimately restore central vision, so that people with macular degeneration can regain the ability to read and recognize faces," says Botond Roska, Director at IOB, and one of the paper's corresponding authors.  

Emitted by every object in the universe, infrared light is invisible to the naked human eye, though it can be sensed as heat. Longer infrared wavelengths can cook food. But near-infrared light is closer to the human visible spectrum and is cooler by comparison. Specialized cameras can use it to detect objects in the dark. Certain animals, including snakes and bats, use heat-sensitive proteins called transient receptor potential channels (TRP) to detect infrared radiation emitted by their prey.  

Inspired by this example from nature, the IOB team wanted to equip eye cells with temperature sensors that convert near-infrared light into visual imagery. The trick was to get blind retinal cells to express and use TRP, which is a protein that they do not ordinarily make. To accomplish this feat, the researchers created a gene therapy made of several components: an engineered stretch of DNA containing a promoter followed by the gene that codes for TRP, a gold nanoparticle that absorbs near-infrared light, and an antibody that binds the nanoparticle to the TRP protein. They used a viral vector to get the therapy into retinal cells. When new TRP proteins reach the cell surface, the system is ready. The nanoparticles absorb near-infrared light, and then emit a small amount of localized heat. In response, TRP channels open up and transmit electrical signals that go to visual processing centers in the brain. The nanoparticles are "tunable," meaning they can be designed to absorb light at any near-infrared wavelength. And the DNA promoter ensures that TRP is expressed only by a subset of targeted cells, instead of throughout the entire retina.

The therapy was then tested in two model systems: engineered mice that develop blinding retinal degeneration within four weeks of age, and live retinas collected from human multiorgan donors.

In the first case, the researchers studied how exposure to near-infrared light alters "lick rates" in blind mice. Thirsty mice will lick in anticipation of being able to drink. During training exercises, a near-infrared light cue was given to indicate that water will follow. Lick rates increased every time the animals were exposed to light, indicating a measurable behavioral effect.  Near-infrared light-evoked signals were also detected in multiple retinal layers and in visual processing centers of the mouse brain.

The second set of experiments was conducted using an approach developed by Arnold Szabo, a co-author of the paper and Assistant Professor at the Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary. Using his method, human retinas can be kept alive for months, though blindness sets in a day or so after death. Experimental results showed that following treatment with the gene therapy, near-infrared light exposures reactivated the retina's visual circuitry.

The new paper builds on ongoing efforts by IOB researchers and their collaborators in Paris to treat total blindness with optogenetic therapy. Entailing the delivery of light-sensitive proteins delivered by viral vectors, this approach is currently in clinical trials, but is unsuitable for macular degeneration. It relies on eye goggles that project bright visible light onto the retina that would overwhelm patients who have merely lost central vision.

The clinical development will also make use of light-projecting goggles, similar in style to Google glass. "But for macular degeneration, you need light of another wavelength that functioning cells in the retina are unable to see," says Dasha Nelidova, a postdoctoral fellow in in the lab of Botond Roska, and the paper's first author. "This is the first therapy that creates light sensitivity outside the spectrum normally visible to the human eye. We hope that one day we can resensitize the macula to light in patients who have remaining peripheral vision.”

Original publication

Restoring light sensitivity using tunable near-infrared sensors
Dasha Nelidova, Rei K. Morikawa, Cameron S. Cowan, Zoltan Raics, David Goldblum, Hendrik P. N. Scholl, Tamas Szikra, Arnold Szabo, Daniel Hillier, Botond Roska
Science  05 Jun 2020: Vol. 368, Issue 6495, pp. 1108-1113
DOI: 10.1126/science.aaz5887