Light-Activated RPE65 Inhibitors Enable On-Demand Visual Cycle Control

Area of Science:

• Ophthalmology
• Pharmacology
• Biochemistry

Background:

• Light is crucial for vision but can worsen blinding diseases linked to the visual (retinoid) cycle.
• Current visual cycle modulators (VCMs) cause side effects like night blindness due to chronic suppression.

Purpose of the Study:

• To develop novel VCMs activated by visible light through Z→E photoisomerization.
• To create light-inducible VCMs for targeted, on-demand inhibition of the visual cycle.

Main Methods:

• Synthesized azobenzene-containing VCMs, including (Z)-9.
• Investigated the photoisomerization of (Z)-9 to its active E-configuration using visible light.
• Assessed the efficacy of (E)-9 in protecting the retina from toxicity and its pharmacodynamic duration compared to emixustat via electroretinography.

Main Results:

• (Z)-9, a weak RPE65 inhibitor, becomes potent upon light-activated Z→E isomerization.
• (E)-9 demonstrated retinal protection against visual cycle toxicity.
• Oral administration of (E)-9 exhibited a shorter duration of action than emixustat.

Conclusions:

• Established posterior-segment photopharmacology using light-activated VCMs.
• Developed a blueprint for therapies mitigating daytime toxicity while preserving night vision.
• Demonstrated the potential of light-activated VCMs for safer, more effective treatment of blinding retinopathies.