The results from a clinical trial using optogenetics to treat a patient with retinitis pigmentosa show that the therapy was able to partially restore visual function. The PIONEER study is a collaborative effort led by an international research team. The researchers include José-Alain Sahel, distinguished professor and chairman of ophthalmology at the University of Pittsburgh and founding director of the Institut de la Vision, and Botond Roska, founding director at the Institute of Molecular and Clinical Ophthalmology in Basel, and professor at the University of Basel. The results of the study are reported in Nature Medicine.
"The findings provide proof-of-concept that using optogenetic therapy to partially restore vision is possible," said Roska.
Retinitis pigmentosa (RP) describes a group of genetic disorders that cause a breakdown of cells in the retina of the eye. "The retina is a biological computer at the back of your eye," explained Roska. He used the analogy of a hamburger to depict the functional anatomy of the retina: "The top bun is a photosensitive layer, and the bottom bun is the ganglion layer, which forms the optic nerve and talks to the rest of our brain." In between the two buns, where, in a burger you find salad, tomato and meat, in the retina, you find a computational layer that computes visual information. Photoreceptors sense light and use proteins, known as opsins, to deliver the visual information to the brain for processing. "In RP, the photosensitive layer – the top bun – is damaged, but the rest of the burger is intact," said Roska. There is no light-sensing capability, and the retina is blind.
RPs are monogenic disorders, meaning they are caused by a single abnormal gene. The specific type of RP that a patient is diagnosed with will depend on the genetic mutation they possess. This variation makes it challenging to develop treatment strategies for RP disorders.
Over recent years, there has been an increased amount of research exploring the use of gene therapy for inherited vision disorders, including optogenetic strategies. In optogenetics, cells are genetically altered such that they express light-sensitive channels – known as channelrhodopsins – therefore rendering the cells sensitive to light. The method has largely been utilized in neuroscience research as a method to "turn" neurons on and off to investigate their function. However, it may also possess clinical value as a therapeutic tool in RP, where the photosensitivity of the retina is diminished.
"In optogenetic therapy, we create an artificial photosensitive layer in the blind retina. We do this by taking light sensors from microbes and delivering them to the blind retina using gene therapy via an injection. There are different kinds of optogenetic therapies depending on which layer we [want to] photosensitize," said Roska.
Optogenetic therapy: A case study
In the clinical trial reported in Nature Medicine, Sahel and colleagues delivered an optogenetic therapy targeting the ganglion cells to a 58-year-old blind male who had been diagnosed with RP 40 years ago. The gene for a light-sensing channelrhodopsin, known as ChrimsonR, was delivered to the worst-seeing eye using an adeno-associated viral vector. "We chose ChrimsonR, which has one of the most red-shifted action spectra among the available optogenetic sensors because amber light is safer and causes less pupil constriction," the authors write in the paper. "Once the [ChrimsonR] protein was expressed, we needed to activate this protein. We developed goggles that are able to capture light through a camera that is functioning like the visual system," said Sahel. The camera captures and then projects images on to the retina at amber light wavelengths to activate the ChrimsonR proteins.
The team waited five months after the injection to begin training the participant with the goggles, enabling the ChrimsonR protein expression to stabilize within the ganglion cells. "Over several months the patient spontaneously reported that he could see some stripes when he was looking on the street," said Sehal.
Sehal and colleagues conducted several different experiments under laboratory conditions to evaluate whether the optogenetic therapy had triggered an improvement in visual function in the patient. One example of the tests used involved detecting, locating and then touching a large notebook, or a small staple box.
"The patient was able to detect objects on a table, grasp the objects and count them," explained Sehal. This was only when he was wearing the goggles; without them, he was not able to perform the exercises. He touched the notebook 36 times out of 39 separate tests (a score of 92%); however, he could only pick out the staple box 36% of the time.
"We wanted to know that this corresponded to brain activity," said Sehal. The researchers decided to conduct a non-invasive electroencephalography (EEG) scan of the patient whilst asking the patient to press a button to indicate whether a glass tumbler was present on the table in front of him, or whether it had been removed. "It was possible to show that visual behavior correlated with brain activation corresponding to visual function," Sehal added.
A mutation-independent treatment strategy
The authors state in the publication that, collectively, the psychophysical and neurophysiological evidence presented "suggest that the optogenetic stimulation of human retinal ganglion cells by a light-projection system linked to a camera is a promising way to partially restore vision in blind patients affected with advanced RP". The 58-year-old participant is the first patient entered into the PIONEER trial.
PIONEER is a three dose-escalation study to determine the safety of the optogenetic gene therapy. The doses that will be investigated are: 5.0 × 1010, 1.5 × 1011 and 5.0 × 1011 viral genomes per eye, with three patients allocated to each cohort. The patient presented in this report received the lowest dose of 5.0 × 1010 viral genomes. "Clearly we hope that a higher dose would provide better results, but at such a low dose the patient was already able to get back some vision," said Roska.
"Two other patients in the cohort were treated in London. Because it was safe, a second group of patients were treated at the middle dose, and it was also safe. The third cohort is now starting. Because of COVID-19, only this patient [at the center of the Nature Medicine paper] was treated in time to be able to test the goggles, be trained and to be brought back the hospital to be tested properly," explained Sehal.
The optogenetic method tested in the PIONEER trial is mutation-independent; which means that blind patients with different types of neurodegenerative photoreceptor diseases – and an intact optic nerve – would potentially be eligible for treatment. "However, it will take time until this therapy can be offered to patients,” concluded Sehal.
Reference: Sahel JA, Boulanger-Scemama E, Pagot C, et al. 2021. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med. doi: 10.1038/s41591-021-01351-4.