Despite being the most common cause of blindness in people of working age - affecting 1 in 3000 –inherited retinal degeneration (IRD) has so far proven to be extremely challenging to address.
Due to the remarkable genetic diversity of this condition, currently available gene therapy for IRD is only suitable to treat a handful of cases, and a significant percentage of patients have no genetic cause clearly identified despite thorough clinical investigation.
Furthermore, gene-specific therapeutic approaches may be inappropriate for patients at the end stages of the disease, who have already, and irreversibly lost key cellular structures required to restore vision.
As a result of the above methodological issues, vision scientists are quickly turning to gene-independent alternative approaches applicable to a larger cohort of patients affected by IRD.
One such approach is optogenetics, a recently developed biological technique targeting secondary (e.g., bipolar cells) or tertiary neurons (e.g., retinal ganglion cells) and effectively converting them into novel photoreceptors through the expression of light-sensitive proteins known as Type I or Type II opsins.
Professor Matthew Simunovic is Professor of Ophthalmology & Visual Science at the Save Sight Institute where he leads the Retinal Disease and Rescue Group.
Additionally, he is a senior consultant ophthalmic surgeon at Sydney Eye Hospital and the Sydney Children's Hospitals Netork where he subspecialises in surgery and diseases of the retina.
Dr Lay Khoon Too is a senior scientist of the Retinal Disease and Rescue Group working on gene- and cell-based approaches to restore vision loss caused by retinal diseases, such as retinal dystrophies and age-related macular degeneration.
Led by Professor Matthew Simunovic, Head of the Retinal Disease and Rescue Group, the SSI in-house research team investigated the effects of a promising and newly described Type I opsin called bReaChES to restore vision in a murine model of severe, early-onset retinal degeneration.
As Professor Simunovic explains, the rationale behind the choice of this specific type of opsin as a suitable candidate optogenetic molecule in the context of visual restoration was twofold.
First, the broad sensitivity spectrum of this protein, approaching approximately 590nm, closely resembles the peak sensitivity of human vision under daylight conditions.
Secondly, bReaChES’ high channel conductance and rapid temporal responses confer improved light sensitivity with faster kinetics than other Type I opsins.
The results of these pioneering efforts were the object of a recent publication in the flagship journal Scientific Reports and the first author, Dr Lay Khoon Too, has also been awarded the Australasian Gene and Cell Therapy Society's Best Gene Therapy Paper prize 2022 for her impressive endeavour.
This remarkable work elegantly demonstrates the long-term effectiveness of the optogenetic treatment in the animal model.
Concretely, intravitreal injection and subsequent expression of bReaChES in dystrophic mice resulted in restoration of retinal sensitivity, cortical activation, and behavioral responses to an ethologically relevant stimulus.
Professor Simunovic points to the numerous advantages of this technique in treating retinal degeneration, especially its straightforward surgical delivery and its high spatial and temporal sensitivity making it potentially compatible with indoor lighting.
Building on these exciting results, and thanks to the financial support of the NHMRC, Professor Simunovic and colleagues plan to spend the years to come translating and adapting this optogenetic paradigm to restore inherited retinal degeneration in humans.
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