Researcher Botond Roska, MD, PhD, shared with colleagues his initial work on genetics and the retina at a conference in 2008, and was met with room-sized skepticism. “And they told me that I’m cuckoo … ‘this is not something that ever will happen in ophthalmology,’” he says he was told.
One fellow researcher, though, sensed definite potential for the emerging field of optogenetics. Dr José-Alain Sahel approached Dr Roska. “And José was the first; he came to me and said, ‘You know, let’s work together and bring it to patients,’” he continued. And now, the latest research led by Dr Sahel released in May is drawing worldwide attention.
This study demonstrates the first case of partial visual recovery for an individual with a neurodegenerative disorder. A male patient, 58 years of age, who was diagnosed with retinitis pigmentosa (RP) 40 years ago can now locate and count objects. The open-label phase 1/2a PIONEER study (ClinicalTrials.gov Identifier: NCT03326336) is a multicenter, nonrandomized project conducted by investigators in France, the UK, and the US. It is published in Nature Medicine, and may ultimately represent the way ophthalmologists will treat this genetic disorder.
PIONEER demonstrates outcomes for the first participant of a larger group. Three cohorts with 3 participants each, and an extension cohort are being treated with two-part therapy. The first part is an intravitreal injection of serotype adeno-associated viral vector that stimulates foveal ganglion cells. The optogenetic vector carries a light-sensing protein, ChrimsonR combined with the red fluorescent protein tdTomato, to cells so they may detect light. The peak wavelength for ChrimsonR-tdTomato is approximately 590 nm.
In the second part, amber light is projected to the eye from a goggle-mounted system that includes both projector and a forward-facing camera. The camera senses in a scene each pixel’s change in intensity, an “event.” A small pocket-sized computer converts events to the monochromatic image projected in real time to a “circular retinal area of 10° of visual angle.”
Drs Sahel and Rosko emphasize that vision rehabilitation is vital. Systematic visual training began for this patient 18 weeks after injection, including centering the gaze on projected light. His training began slowly, but then progressed and he became enthusiastic, Dr Sahel said. “Now he wants to be able to be cooking and other things that he didn’t do before,” he added.
The patient completed 15 sustained post-injection goggle-training sessions.
This study’s approach is mutation-independent — it does not matter what specific mutation the patient has. Participants cannot have more than light perception to be included. Most patients have at least some light perception, indicating a functioning optic nerve. “But in theory, as long as you can show that you still have ganglion cells in the retina — and we have imaging techniques that will show that very clearly — then it’s still theoretically possible to restore some vision,” Dr Sahel said.
As far as how old a patient must be to benefit, he believes there is no upper age limit. The current study examines acquired blindness in those 18 to 75 years of age. If a child is blind from birth, it is still unknown if the visual cortex could handle restored images. Both investigators say there may be some evidence future optogenetic therapy could benefit children; it should not be ruled out.
Recipients of optogenetic treatment need to be screened. Optical coherence tomography (OCT) can help in assessing structural requirements. RP diagnosis also should be confirmed. A possibly overlooked, but important part of the screening process relates to patient expectations. Functional visual improvements are useful, but are not full vision, the investigators warn.
“Some patients are so desperate to get back their vision, but there is a high risk that they would be extremely disappointed if they don’t get what they are expecting … so we are quite careful in my center in Paris,” Dr Sahel said. Two independent clinical psychologists meet with participants. They address each patient’s understanding of best possible outcomes, and only report to researchers if there may be a psychological risk for the participant.
Initial Study Results
The first patient began to report changes in his vision at about 7 months as stimulation by ChrimsonR-tdTomato stabilized. Three visual tests were performed at Streetlab, Institut de la Vision, Paris (where Dr Sahel is founder and director) using various conditions: both eyes open without light-projecting goggles, treated eye open without goggles (monocular), and treated eye open with stimulation from goggles.
In the first test to perceive, locate, and touch a larger notebook or smaller staple box on a white table, the participant was not able to detect objects or complete tasks in the first 2 conditions. But in the treated eye, stimulated condition, he located the notebook 92% of the time. Success rate depended on size of the object (P <.001). When objects were presented in 3 contrast levels, his ability to do the 3 tasks was similar (P =.29).
The second test consisted of perceiving, counting, and pointing to either 2 or 3 tumblers, 6 cm diameter by 6 cm tall. Similar to the first test, the participant could not detect tumblers in the first 2 conditions. But, in the stimulated treated eye condition, he perceived and correctly counted the objects in 63% of trials and located them 58% of the time. Here, results were also alike at different contrast levels (P =.20).
Injections and Training
Patients can undergo the vector injection in an operating room or in a procedure room. In addition to infection risk with intravitreal injections, special care has to be taken to discard genetic material and instruments that contact it.
For this reason and the comprehensive post-injection training, the investigators believe therapy needs to take place — not necessarily in a research center — but some type of specialized center with a clinical, surgical, and rehabilitation team. “So, it’s quite unlikely that this type of therapy would be done by every single ophthalmologist in every single place,” Dr Sahel said.
The complexity of 2-part therapy requires a cadre of specialists. Two integral experts are an occupational therapist, as well as a low vision specialist: an optometrist or orthoptist.
In the study’s third vision test, the patient wore an electroencephalography (EEG) cap with passive electrodes to measure cortical activity while he distinguished between presence or absence of the tumbler. In the first 2 conditions without goggles, he could only correctly identify the presence of the tumbler 5.8% of the time, but when the treated eye was stimulated by goggles, his success rate improved to 41% (P <.001). A spectral analysis of EEG activity revealed the greatest difference between object and no object distinction was found “above the occipital cortex contralateral to monocular stimulation,” especially at 14 Hz.
Since the first 2 visual tests were conducted 5 months before the third test, visual gain shows stability, according to the study. Also, the EEG acted as neurophysiological evidence of regained visual function. Outside of the lab, the patient also identified — with googles — the number of white stripes in crosswalks, and location of daily-used objects such as furniture, a plate and mug, and a door in the hallway.
In OCT images taken before the injection, and at 25 and 52 weeks afterwards, bilateral hypo-reflective cyst-like spaces typical of RP were evident. What should ophthalmologists look for in scans? Drs. Roska and Sahel explained the objective is to check for stability. This participant presented with intermittent cysts. “But they are really minimal and stable; no change,” Dr Sahel added. “So, no impact of the therapy on that.”
Retinal anatomy was stable during the study period. Also, after the vector injection there was no intraocular inflammation, as well as no adverse events during follow-up.
The investigators are now exploring possibilities for a camera and projector to be mounted on spectacles rather than on goggles. Dr Sahel explained that it is unlikely to be a standard type of spectacle purchased in an office. Eyeglass manufacturers could produce a similar medical device, but it would not be practical, because optogenetic therapy is a combination of injection and evolving device training.
Dr Roska thinks it may be difficult for companies to address the multiple ways this system can be programmed, and it is probably enough for one or two manufacturers to supply the device for everyone.
He added that most people do not like to have electronic implants in their brain, and this type of system presents options. “So, you have a massive computational power here,” he said. “You can change it any way you want — the image that is projected to the retina — but you don’t have to do it within the eye. It’s outside.”
The Beauty of Science
Dr Sahel underscores that a project such as this can launch from a basic discovery not expected to produce new treatments — being broad-minded is critical. He added that breakthroughs can also start “with the beauty of science, which is sometimes friendship, just working together like we did with Dr Botond to drive this project from a ‘crazy idea’ to an initial achievement.”
Also, it is important to bring together a large team, such as the volunteers and professionals who contribute, from gene therapy and biotherapy development to medical device design and rehabilitation, to cognitive and computational neuroscience.
“I would emphasize that this is 15 or 16 years of constantly working together and constantly knowing that it might not happen, Dr Roska explained. “So, it was not clear at every point that this would work. But it was really driven by José’s optimism that patients need it, and the technology (advancements), and the understanding of the retina.”
Disclosure: Some study authors declared affiliations with the biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Sahel JA, Boulanger-Scemama E, Pagot C, et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nature Medicine. May 24, 2021. doi:10.1038/s41591-021-01351-4