Defining a novel way of treating severe blinding conditions

Vision loss is a major cause of morbidity. Vision loss due to inherited disease remains one of the most important unmet medical needs in medicine.

A large number of inherited retinal diseases (also called retinal dystrophies) are characterized by a mutation in a single gene that leads to dysfunction and/or degeneration of the light sensitive photoreceptors in the retina, the rods and cones. With the advent of gene therapy, it is possible to introduce, remove or change the genetic material in cells in order to treat diseases.

Optogenetics is a special form of gene therapy. It can make cells light-sensitive via genetically expressed, bacterial light-activated proteins. In certain cases of retinal dystrophies, cone photoreceptors lose their natural ability to sense light, however they remain alive in a dormant stage and can be potentially re-activated with optogenetics.

Optogenetics has already reached the clinic, with human clinical trials underway. These trials however target cells to which photoreceptors only indirectly connect (ganglion cells). Our approach is unique, as we are targeting photoreceptors, not the downstream retinal cells. This method benefits from retinal connections and data processing still being mostly intact.

In this project, we aim to transfer an optogenetic protein (ChrimsonR) to dormant cone photoreceptors, so that they can sense light again. The ChrimsonR protein will be delivered to cells using adeno-associated vectors (AAVs), which work as miniature Trojan horses and transport ChrimsonR to cones. Their safety and efficacy have already been demonstrated in several clinical trials, including clinical trials in ophthalmology. They can be injected underneath the retina to reach the target cones (Figure). Our group showed that AAV-mediated delivery of an optogenetic protein restores light responses in blind mice and re-activates the existing retinal circuitry.

At IOB, our researchers and clinicians work hand in hand to bring this approach to patients and launch a clinical trial. First, we will optimize the lead candidate clinical product, to achieve the highest efficiency of cone targeting. We will then expand our previous studies to confirm efficacy and safety of the product in human skin-cell derived retinal organoids (‘organ in a dish’ system) and in human retina explants (from multi-organ donors). IOB teams have the specific expertise to perform all these experiments. In collaboration with the Eye Clinic of the University Hospital Basel we will also recruit and characterize potential patients who could benefit the most from such a treatment. Upon permission by the regulatory agencies, the first in-human clinical trial will be conducted in Basel on a group of patients with severe vision loss.

Based on our previous experience and data from preclinical experiments, we expect to see significant vision restoration in blind patients. Our project has the potential to be broadly applicable, as patients with different genetic mutations could be treated, as long as they still have remaining cone photoreceptors. This strategy has the potential to define a novel way of treating severe blinding conditions and holds great promise to restore eyesight in the blind.

Project Leader: Bence György, Head of the IOB Clinical Translation Group

Team members