Octant, Mass Eye and Ear, Harvard Medical School, and the Broad Institute measured protein trafficking for all 6,612 possible RHO missense variants, published today in Science Advances.
EMERYVILLE, CA– July 29, 2026 – Researchers from Octant, Mass Eye and Ear, Harvard Medical School, and the Broad Institute of MIT and Harvard have published a comprehensive functional map of genetic variation in rhodopsin, a major cause of autosomal dominant retinitis pigmentosa, or RHO-adRP.
Many RHO variants cause disease by disrupting how the rhodopsin protein folds and moves through the cell. Misfolded rhodopsin can become trapped in the endoplasmic reticulum rather than reaching the cell surface, contributing to cellular stress and photoreceptor degeneration.
By integrating results from two complementary deep mutational scanning assays measuring the trafficking of all 6,612 possible RHO missense variants, the researchers generated a cross-validated map of how genetic variation affects rhodopsin folding and trafficking to the cell surface. The study identified hundreds of variants with trafficking defects and showed that poorer trafficking was associated with greater endoplasmic reticulum stress, connecting the functional assays to an established disease mechanism.
“One of the most exciting aspects of this study was functionally analyzing thousands of rhodopsin genetic variants at once,” said Kannan Manian, Ph.D., post-doctoral scholar at Mass Eye and Ear and co-first author. “The study gives us an unprecedented understanding of which variants are harmful and which may be treatable, bringing precision medicine closer to clinical trials.”
The researchers also evaluated YC-001, a prototype non-retinoid small-molecule chaperone, and found that the majority of mis-trafficking variants evaluated showed improved trafficking under the study conditions.
“This project started 15 years ago as an effort to improve interpretation of genetic testing results for patients with inherited retinal conditions,” said Jason Comander, M.D., Ph.D., Director of the Inherited Retinal Disorders Service at Mass Eye and Ear and corresponding author. “Without a genetic diagnosis, patients can miss out on getting a concrete diagnosis, having the opportunity for family planning, learning information about their prognosis and the risk to family members, and can even miss out on joining clinical trials for potential therapies. At the time, I did not imagine that this same deep mutational scanning approach could be used not only for diagnostic purposes, but also for pharmacogenomics and drug discovery. Seeing that this work could lead to potential treatments for patients with inherited retinal disease is incredibly rewarding.”
The findings establish a broader framework in which multiplexed functional genomics can connect genotype, molecular mechanism, and therapeutic response across genetically heterogeneous diseases.
“Rather than treating every RHO variant as a separate problem, this work enables us to group variants into coherent subsets based on the biological defects they share,” said Connor Ludwig, Ph.D., scientist at Octant and co-first author. “By identifying variants that converge on misfolding and mis-trafficking, we can pursue therapies directed at that shared mechanism.”
Octant has applied this framework to OCT-980, an oral small-molecule corrector for misfolding and mis-trafficking RHO variants, now in clinical development.
Publication: Manian & Ludwig, et al. “A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction.” Science Advances. https://www.science.org/doi/10.1126/sciadv.aef3518
Octant is a clinical stage drug discovery company developing correctors for protein misfolding diseases. Octant’s platform, The Navigator, combines high-throughput synthetic biology, generative chemistry, and AI/ML to discover and develop therapeutics against complex cellular mechanisms in human cells. OCT-980 is a small molecule corrector for RHO associated autosomal dominant Retinitis Pigmentosa (RHO-adRP), and Octant’s pipeline includes several other programs across other rare diseases and oncology. For more information visit www.octant.bio.