[FG] György Bence
Head of Research Unit
Prof. Bence György, Prof.
Projects & Collaborations
Gene editing as a therapy for blindness
Research Project | 1 Project Members
The human genome project, completed in 2003, allowed us to read the information stored in the human genome. Two decades later, gene editing, now enables not only to read, but also to edit the genome by precisely changing a single nucleotide out of the 3 billion base pairs.
Stargardt disease is one of the leading causes of blindness in juveniles. The vast majority of the patients carry a mutation in the ABCA4 gene. The protein product of this gene is responsible for removing a toxic by-product produced upon normal visual function in the retina, the light sensitive layer at the back of the eye. Affected patients slowly lose their central vision, which severely impairs their ability to read, recognize faces or to see colors. Currently, there is no treatment available for this seriously debilitating disorder.
With the advent of gene therapy, it is possible to introduce, remove or change the genetic material in cells in order to treat diseases. Base editing, a novel but highly promising approach can directly change the faulty genetic code and revert disease causing mutations back to normal. This process is similar to correcting a single typo in a text. Base editors are complex molecular machines that are guided to the target gene of interest (ABCA4 in our case) via a small nucleic acid molecule.
Together with BEAM Therapeutics (Cambridge, MA, USA), IOB developed a base editing approach to treat Stargardt disease. We have demonstrated that base editing can correct the underlying mutation in the ABCA4 gene, with very high precision. We reached base editing correction rates up to 60% in cone photoreceptors, which is way above the threshold required for therapeutic level. It is expected that correction of ~20% of cones is expected to be therapeutic and provide significant visual benefit to patients. The direct genetic correction of the underlying genetic problem holds promise for patients with Stargardt disease and can be applied to other ocular diseases in the future.
Optogenetics for vision restoration
Research Project | 1 Project Members
Vision loss is a major cause of morbidity and a major fear for many people. The main causes of vision loss originate from the retina, the light-sensitive layer at the back of the eye. Blindness is currently an untreatable medical condition and represents a significant unmet medical need.
Optogenetics is a form of gene therapy that uses light-sensitive proteins to control biological processes. This technique can be particularly useful for vision restoration, as remaining cells in the blind retina can be made light-sensitive through targeted expression of an optogenetic protein.
We developed an optogenetic vector that can selectively express a light-sensitive protein in human cells and activate them. We used a human retina model to demonstrate that this approach can restore retinal light sensitivity and retinal computations. The optogenetically treated retina responded to light stimulation just as normal human retinas do.
Our goal is translate this work to the clinic. We founded a spinout company, RhyGaze AG, which will further develop the therapy with a goal of initiating a clinical trial. Our approach has the potential to restore high-acuity vision in blind patients who retain cones in the fovea.
Translational Clinical Research
Umbrella Project | 1 Project Members
Clinical research complements translational projects and are aimed at closing important clinical gaps.
Optogenetics is a highly promising novel therapeutic approach, that targets light sensitive proteins to certain cell types in the retina, in order to reactivate them. A recent study showed that a blind patient, who received an injection with an adeno-associated viral vector (AAV) carrying an optogenetic protein, regained some vision. This suggests that restoring vision in advanced forms of retinal degeneration using optogenetics is possible. This approach expressed the optogenetic channel in ganglion cells, the axons of which form the optic nerve. It would be more ideal to express the optogenetic channel in cone photoreceptors, because: (1) cones are natural light sensors, and (2) the organization of cones in the retina would allow for correct image formation. Re-sensitizing cones in blind mice led to restoration of retinal light responses and retinal information processing, which translated to detectable visual acuity and visually-guided behavior. However, until recently, targeting human cones with optogenetic channels has not been possible. We recently developed a cone-targeting AAV vector that restored retinal light responses and visual computations in the human and primate retina. This gene therapy program is being brought forward to clinical development to restore vision in blind patients.
However, little is known about the biology of preserved cones in blind humans. Post-mortem histology analysis and case series using ocular imaging demonstrated the presence of targetable cones in some blind patients. To analyze cone presence in a larger population, we launched a world-wide, cross-sectional ocular imaging study (EyeConic-IRD, NCT05294978, https://eyeconic.iob.ch/), where we already collected data from 434 eyes from 286 IRD patients. Importantly, 61% of the eyes of EyeConic-IRD subjects were above the foveal preservation threshold suggesting that cone-targeted optogenetics might be appropriate for 2/3 of the patients.