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Optogenetic therapy restored partial vision in a blind 58-year-old man diagnosed with retinitis pigmentosa almost 40 years ago, according to a case report from the ongoing PIONEER study.

In this open-label phase I/IIa study, intraocular injection of an optogenetic sensor-expressing gene therapy vector combined with use of light-stimulating goggles was found to partially restore visual function in a patient with visual acuity of only light perception, reported José-Alain Sahel, MD, of the University of Pittsburgh, and colleagues in .

Retinitis pigmentosa is an inherited neurodegenerative disease that breaks down light-receptive cells in the retina and can lead to complete blindness. More than 2 million people worldwide are affected by this progressive disease. There is no approved treatment, except for a gene replacement therapy that works only in an early-onset form of the disease caused by a mutation in the RPE65 gene.

Optogenetics is a mutation-independent approach for restoring visual function at the late stages of retinitis pigmentosa.

"The approach was to activate the ganglion cells in the patient, who had already been blind from retinitis pigmentosa," Sahel explained at a press conference, "transform remaining surviving cells still connected to the visual brain, and activate them using optogenetics."

An optogenetic vector encoding the light-sensing channelrhodopsin protein ChrimsonR fused to the red fluorescent fusion protein tdTomato was administered via a single intravitreal injection into the patient's worse-seeing eye to target foveal retinal ganglion cells, with tdTomato included to increase the expression of ChrimsonR in the cell membrane, the authors explained.

"Light-stimulating goggles capture images from the visual world using a neuromorphic camera that detects changes in intensity, pixel by pixel, as distinct events. The goggles then transform the events into monochromatic images and project them in real time as local 595-nm light pulses onto the retina," they added.

"The work is the result of a 13-year collaboration between our two groups," said co-author Botond Roska, MD, of the Institute of Molecular and Clinical Ophthalmology Basel in Switzerland.

This approach is distinct from current ocular gene replacement and editing therapies, noted Roska. "We look for blind patients, whereas those approaches try to slow down the loss of vision, and would not work in blind patients because the cells are dead."

Researchers waited over 4 months after the injection to allow the expression of ChrimsonR-tdTomato in foveal ganglion cells to stabilize, and then started the patient on visual training using the light-stimulating goggles at , a vision rehabilitation center that uses naturalistic platforms. Seven months after beginning training, the patient reported being able to see some black and white stripes -- a cross walk -- on the street.

When he was brought back to Streetlab for three visual tests, "he was able to detect objects on the table at a distance, and then [as per the testing protocol] grasp different types of objects in different contrasts and lighting," said Sahel.

Multichannel electroencephalographic recordings of the occipital cortex "suggested that retinal activity evoked by the optogenetic stimulation of the retina propagates to the primary visual cortex and modulates its activity," the authors wrote.

"Interestingly ... under stimulated monocular condition, the patient reported 'vertical vibrations' when perceiving an object ... [which he] did not report when wearing the light-stimulating goggles before the injection," they noted; these may be caused by the localized light pulses sent to the eye.

"It appears to be a positive, rather than a negative, sign because the patient said he was looking for it, saying that it seems like an exclamation mark," said Roska.

The injections were not associated with any intraocular inflammation, changes in the anatomy of the retina, or ocular or systemic adverse events. "Once the safety study is confirmed, we can enter the validation phase with many more patients, hopefully within the next 5 to 10 years," said Sahel.

During the press conference, Sahel and Roska noted that 1 year after the first test (the assessment process was extended by COVID-19-related delays), the treatment is still working, although they stressed that the patient's vision is not clear enough for facial recognition or reading.

Optogenetics is simpler, less invasive, and more easily adjusted, since the software and hardware are all outside the eye: "A major advantage of optogenetics over electronics in my view is that we can target specific cell types in the brain regions, whereas with electronics, you pass current and whatever cells are on receive it," said Roska.

have a place for , noted Sahel. "Optogenetics wouldn't work for blindness due to trauma or untreated glaucoma, or for anyone without ganglion cells, so protection of remaining cells is important."

Optogenetics may have the potential to provide a better level of resolution in earlier-stage patients, who probably have more ganglion cells and better retinal structure of the retina, explained Sahel. "High-resolution imaging tools allow us to see the structure of the retina in 3D so we can detect the number of cells and quality of the tissue to determine what to expect."

"This marks the birth of a new scientific field, namely visual rehabilitation," said Roska. "The brain has to learn a new language because retinal ganglion cells are sending it new messages, and patients have to adapt. We are learning from the patients themselves how they are using vision."

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