Scientists have identified two non-retinoid compounds that may be able to treat retinitis pigmentosa (RP), a group of inherited eye diseases that cause blindness. The compounds were discovered by Beata Jastrzebska, PhD, at Case Western Reserve University, and colleagues, using a virtual screening approach to look for molecules that bind to and stabilize the structure of rhodopsin, to improve its folding and movement through the cell. Tests showed that the identified compounds prolonged the survival of photoreceptors in a retinitis pigmentosa mouse model for rod opsin misfolding, and protected retinas against light-induced degeneration in animals vulnerable to bright light injury.
Jastrzebska and colleagues reported on their discovery in PLOS Biology. In their paper, titled “Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa,” the team concluded “Together, our findings suggest that the molecules identified in this study represent promising lead compounds for the development of precision therapeutics for RP and other visual retinopathies.”
Inherited mutations that disrupt protein folding are responsible for a variety of protein conformational diseases (PCDs), the authors wrote. “One of the most important known PCDs is retinitis pigmentosa (RP), which is a blinding disease associated with mutations in the rod opsin (RHO) gene among other retina-specific genes.” In retinitis pigmentosa the retina protein rhodopsin is often misfolded due to genetic mutations, causing retinal cells to die off and leading to progressive blindness. Small molecules to correct rhodopsin folding are “urgently needed” the team continued, to treat the estimated 100,000 people in the US with the disease.
Current experimental treatments include retinoid compounds, such as synthetic vitamin A derivatives, which are sensitive to light and can be toxic, so have several drawbacks. “Though several approaches have been previously employed to identify small molecules that rescue the expression of P23H and other misfolded Rho variants, most of these compounds have poor pharmacological properties or bioavailability, thus there are still no approved therapeutics for retinitis pigmentosa.”
In their newly reported study, the researchers utilized virtual screening to search for new drug-like molecules that bind to and stabilize the structure of rhodopsin to improve its folding and movement through the cell. “… we utilized virtual screening to search for drug-like molecules that bind to the orthosteric site of rod opsin and improve its folding and trafficking,” they explained.
Two of the identified non-retinoid compounds, JC3 and JC4 met the required criteria and had the ability to cross the blood-brain and blood-retina barriers. “In this study, we describe 2 new pharmacochaperones, JC3 and JC4, which bind reversibly to ligand-free opsin and modulate opsin properties without regulation by light,” they noted. The team tested the compounds in the lab and showed that they improved cell surface expression of rhodopsin in 36 of 123 genetic subtypes of retinitis pigmentosa, including the most common one. “Using deep mutational scanning,
we compared the effects of these compounds on the expression of 123 known clinically relevant RHO variants and showed that these compounds appear to be effective against multiple variants that could be effectively corrected by 9-cis-retinal, and a subset of variants that are distinct from those the most responsive to retinoids.”
Additionally, the compounds protected against retinal degeneration in mice with retinitis pigmentosa. “We validated the therapeutic potential of these compounds in 2 mouse models of retina degeneration, Abca4-/-Rdh8-/- mice, a model of acute light damage, and in an RP model, P23H Rho knock-in mice,” they explained. “ … the phenotypic effects of JC3 and JC4 in Abca4-/-Rdh8-/- and RhoP23H/+ mice provide compelling evidence of the therapeutic potential of these compounds.” Importantly, they reported, treatment with either compound improved the overall retina health and function in these mice by prolonging the survival of their photoreceptors. They added that the two compounds “… offer considerable translational potential for the development of precision therapeutics for RP and other visual retinopathies.”
The team acknowledged that additional studies of the compounds or related compounds are needed before testing the treatments in humans. They further noted, “Inherited mutations in the rhodopsin gene cause retinitis pigmentosa (RP), a progressive and currently untreatable blinding disease. This study identifies small molecule pharmacochaperones that suppress the pathogenic effects of various rhodopsin mutants in vitro and slow photoreceptor cell death in a mouse model of RP, offering a potential new therapeutic approach to prevent vision loss.”
