Small Molecule Discovery for RP

Although several therapeutic approaches have already been investigated for treating retinitis pigmentosa (RP) genetically, the compounds previously identified have all fallen short of providing an approved treatment for the group of inherited diseases, mainly due to bioavailability issues or their poor pharmacological properties.

Now, a PLOS Biology study investigating drug-like molecules that might be used to suppress the pathogenic effects of misfolded rhodopsin – a retina protein that can be misfolded by genetic mutations, leading to RP – has discovered two unique compounds that might be able to treat the disease.

“I have worked on rhodopsin for more than 20 years,” says study author Beata Jastrzebska, explaining what initially drew her to studying pharmacological effects on the protein. “At first, my studies concentrated on basic questions related to its structure-function relation. However, later in my career I became more interested in translational aspects of my discoveries. Mutations in the rhodopsin (RHO) gene are the most prevalent cause, accounting for ~20-30 percent of autosomal dominant RP (adRP) and ~10 percent of all RP cases.”

The most clinically relevant mutations of RHO are shown to “cause protein misfolding and aggregation in the secretory pathway, leading to cellular toxicity aggregation,” says Jastrzebska. “Despite ongoing research, there is still no cure currently available, highlighting the urgent need for therapeutic strategies to prevent vision loss in RP patients carrying RHO mutations.”

Aided by the Small Molecule Drug Discovery (SMDD) Core at Case Western Reserve University, Jastrzebska and other researchers used computer-aided virtual screening processes to identify two non-retinoid compounds that could be used effectively in a mouse model of RP. “These two molecules were selected from among other hits due to their predicted ability to cross the blood-brain barrier, a critical property when developing drugs intended to reach the retina,” explains Jastrzebska. “Importantly, the drug must also traverse the blood-retina barrier to be effective without requiring direct administration, such as painful injections into the eye.”

The two molecules identified – JC3 and JC4 – “likely stabilize the native structure of mutant opsins and facilitate their proper folding and trafficking to the membrane,” Jastrzebska adds, noting how the compounds might have potentially significant implications for the future of RP treatments, given that, as a small-molecule therapy, they can effectively address the root cause of the disease.

However, while Jastrzebska is optimistic about JC3 and JC4’s potential, she also urges caution: “We still have a long way [to go] before we could even think about [a] clinical trial. This is an exciting discovery; however, the long-term effects of these compounds [still] need to be evaluated.”