These arrestin-1 variants slow retinal degradation by reducing the inhibitory effects of enolase-1 activity, enhancing photoreceptor survival in retinal disease. Inherited retinal diseases (IRDs) affect over two million people worldwide, with their genetic diversity making precision treatment with gene therapy challenging and costly. Current therapeutic approaches focus on targeting specific underlying genetic defects, either replacing or repairing the defective gene. Photoreceptors, among the most metabolically-active cells in the body, are the main energy producers for the neural retina. Arrestin-1, a vital protein in the eye’s response to light, can bind to enolase-1, a key enzyme in the glycolysis pathway in photoreceptors. Enhancing metabolism in the retina through modulating arrestin-1 inhibitory effects entails a promising strategy to alleviate vision loss.
Researchers at the University of Florida have developed modified arrestin-1 variants to reduce the inhibitory effect on enolase-1 catalytic activity, making photoreceptors more resilient to genetic and environmental factors and protecting eye function. The arrestin-1 variants, delivered to the retina via AAV, can prevent or delay the onset of retinal degeneration and vision loss.
Modified arrestin-1 variants are delivered to the retina, improving light sensitivity in patients, targeting inherited retinal diseases, and alleviating vision loss
The arrestin-1 variants comprise amino acid substitutions of select glutamate and aspartate residues. The modified proteins bind enolase-1 with a lower inhibitory effect on enolase-1 catalytic activity, increasing glycolysis and ATP supply to photoreceptors and providing additional metabolic support to surrounding cells in the form of secreted lactate. By raising energy levels, the retina becomes more resistant to damage and degeneration caused by genetic defects.