Two Tiny Molecules Could Save Thousands From Blindness

A new study reveals the potential of two compounds in treating retinitis pigmentosa, a blinding genetic disorder.

These compounds, identified through virtual screening, have shown promising results in stabilizing rhodopsin protein and preventing retinal degeneration in animal models.

Breakthroughs in Retinitis Pigmentosa Treatment

Researchers have identified two promising compounds that may help treat retinitis pigmentosa, a group of inherited eye disorders that lead to blindness. The discovery, published today (January 14th) in the open-access journal PLOS Biology, was led by Beata Jastrzebska from Case Western Reserve University, USA, and her team. These compounds were uncovered using a virtual screening technique.

Retinitis pigmentosa occurs when genetic mutations cause the retinal protein rhodopsin to misfold, resulting in the death of retinal cells and progressive vision loss. Approximately 100,000 people in the United States are affected by this condition, creating an urgent need for treatments that can correct rhodopsin misfolding. Existing experimental therapies often rely on retinoid compounds, such as synthetic vitamin A derivatives. However, these treatments are highly sensitive to light and can be toxic, limiting their effectiveness and safety.

Virtual Screening and Compound Discovery

In the new study, 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. Two non-retinoid compounds were identified that met these criteria and had the ability to cross the blood-brain and blood-retina barriers.

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. Additionally, they protected against retinal degeneration in mice with retinitis pigmentosa.

Promising Results and Future Directions

“Importantly, treatment with either compound improved the overall retina health and function in these mice by prolonging the survival of their photoreceptors,” the authors say. However, they note that additional studies of the compounds or related compounds are needed before testing the treatments in humans.

The authors add, “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.”

Reference: “Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa” by Joseph T. Ortega, Jacklyn M. Gallagher, Andrew G. McKee, Yidan Tang, Miguel Carmena-Bargueňo, Maria Azam, Zaiddodine Pashandi, Marcin Golczak, Jens Meiler, Horacio Pérez-Sánchez, Jonathan P. Schlebach and Beata Jastrzebska, 14 January 2025, PLOS Biology.
DOI: 10.1371/journal.pbio.3002932

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