Project Title:

Optogenetic Approaches For Vision Restoration

Chief Investigator:

Dr Lay Khoon Too

Co-Investigators:

Prof Matthew Simunovic, Dr Dario Protti, A/Prof Leszek Lisowski

Aim

To explore the optogenetic therapy by expressing the long-wavelength cone opsin (LCO) in ON-bipolar cells or retinal ganglion cells of mouse models of inherited retinal degeneration

Methods

Dystrophic and wild-type mice received bilateral intravitreal injections of optogenetic vectors delivering the LCO to either retinal ganglion cells or bipolar cells. Between one- and six-months post-treatment, optogene expression was confirmed via fundus fluorescence imaging, retinal structure was evaluated using optical coherence tomography and vision restoration was assessed using the optokinetic response test, light–dark avoidance behavioural test, and pupillary light reflex.

Conclusion

The study suggests that ectopic expression of LCO in retinal ganglion cells or bipolar cells results in only limited vision restoration under ambient lighting conditions. Significantly, optogenetic expression of LCO driven by hSyn may interfere with residual native vision, potentially limiting its use in certain conditions (e.g. macular degeneration).

 

Lay Summary of Outcomes

Optogenetic vision restoration with type I and type II opsins remains highly promising. Targeting optogenetic therapy to specific secondary- or tertiary-neurons using specific promoters and highly light-sensitive opsins will be essential for optimising optogenetic vision restoration.

 

Key results

Dystrophic mice receiving LCO delivered to retinal ganglion cells via the hSyn promoter or bipolar cells via the hGRM promoter displayed comparable and limited responses to optokinetic and light-dark box testing. The pupillary light reflex of dystrophic mice receiving hSyn-LCO gene therapy was significantly inhibited compared to dystrophic mice receiving hGRM-LCO. Wild-type mice receiving hSyn-LCO showed significantly impaired optokinetic responses, light-dark avoidance behaviour and pupillary light reflex compared to the wild-type mice receiving hGRM-LCO.

 

This research project was funded by ANZSRS in 2024