Feature, Ophthalmic insights, Opinion, Soapbox

Optogenetics in ophthalmology – Prof Matthew Simunovic

At its core, optogenetics uses light to control the activity of neurons. In the context of vision restoration, optogenetics works by inserting the sequence for a light sensitive protein (opsin) into target cells, most commonly via a viral vector.

This protein has the therapeutic effect of conferring light sensitivity to blind retina.

Professor Matthew Simunovic.

“In some respects, it is fair to consider [optogenetics] a biological alternative to the ‘bionic’ retina.”

This therapeutic approach has implications for neurodegenerative diseases, with eye disease at the forefront of this field. In fact, in 2021 the first reported case of partial functional recovery after optogenetic therapy was in a patient with retinitis pigmentosa. Furthermore, positive results have recently been announced for the Phase II RESTORE study.

To understand optogenetics at a deeper level, it’s important to know the concept was initially conceived as a means of controlling neural circuits in the brain by expressing light-sensitive proteins in nerve cells via gene delivery (most commonly using adeno-associated viral vectors). These light-sensitive proteins can be from microbes (so-called Type I opsins) or animals (so-called Type II opsins).

Type I opsins act as both light detectors and as a conduit for ions. They are simple molecules: once activated by light – which converts their chromophore all-trans retinal to 13-cis retinal – they spontaneously return to their light-sensitive state. Type II opsins rely on second-messenger systems: this makes them sensitive (because of inherent second-messenger signal amplification). However, their disadvantage is that they generally have slower kinetics than Type I opsins, and their regeneration relies upon cellular processes.

In the context of vision restoration, optogenetics is most commonly used to confer novel light sensitivity to either second-order (e.g. bipolar cells) or third-order (e.g. retinal ganglion cells) neurons in degenerate retina. This is generally achieved through intravitreal or sub-retinal delivery of adeno-associated virus carrying the sequence for an optogenetic protein.

Optogenetics has also been used to restore light sensitivity to degenerate photoreceptors. The original experiments harnessing optogenetics concentrated on Type I opsins which were maximally sensitive to short-wavelength visible radiation.

However, when it comes to translating this approach into real-world therapies there are inherent problems.

First, the pre-receptoral ocular media strongly absorb these wavelengths. Second, the retinal illuminances required to activate optogenetic treated retinal neurons are close to the safety thresholds for light toxicity.

These problems have been addressed through the identification and development of “red-shifted” high-sensitivity Type I opsins and partly through the harnessing of Type II opsins (e.g. the M-cone opsin).

At the Save Sight Institute in Sydney, our work is currently laboratory-based – using pre-clinical models, including a human retinal explant platform – to develop and assess new candidate opsins for vision restoration.

My group recently published in Scientific Reports on a new Type I opsin, bReaChES, which appears to offer some advantages over previously employed opsins (Optogenetic restoration of high sensitivity vision with bReaChES, a red-shifted channelrhodopsin. Sci Rep 12, 19312 [2022]). We have received funding to develop new approaches to address vision restoration in macular disorders from the Macular Disease Foundation Australia, and in inherited retinal disease (IRD) from the NHMRC.

Optogenetics is an attractive approach because it is ‘causative mechanism agnostic’. That is, it should work for any condition resulting in outer retinal loss, but with preserved retinal ganglion cells (+/- the second-order neurons). This is important because more than 300 genes or loci have been reported in association with IRD – and Australia’s only approved ophthalmic gene therapy, voretigene neparvovec (Luxturna, Novartis), is available for just one of these diseases. Furthermore, around 30% of patients with IRD have no causative gene identified. Finally, nothing can currently restore lost vision in geographic atrophy.

At present, none of the optogenetic approaches investigated would be expected to confer “normal” vision. In some respects, it is fair to consider it a biological alternative to the “bionic” retina. However, the achievable resolution is likely to be superior to bionic retinae that have achieved regulatory approval to date (the best of which, in terms of visual acuity, was manufactured by RetinaAG).

Like any other new drug or therapy, optogenetic approaches must undergo the same rigorous development pipeline, including pre-clinical and Phase 1-3 clinical trials. Some approaches are currently undergoing evaluation in clinical trials. However, major obstacles with certain approaches are inherent insensitivity and lack of gain control/adaptation (which necessitates the use of stimulus goggles). Our lab plans to complete pre-clinical trials in the next year and a half before concentrating on translation to clinical trials in humans. Taking this step will require additional funding support.

Name: Professor Matthew Simunovic
Qualifications: MB Chir PhD FRANZCO
Primary place of work: University of Sydney, Sydney Eye Hospital, Sydney Children’s Hospitals
Position: Professor of Ophthalmology & Visual Science, Senior VMO in Vitreoretinal Surgery
Location: Sydney
Years in profession: 15

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