None approved; QR-421a (Ultevursen) in Phase 2/3
Usher syndrome type 2A is the most common form of Usher syndrome, a genetic disorder that combines sensorineural hearing loss with progressive vision loss due to retinitis pigmentosa. It is caused by mutations in the USH2A gene, which encodes usherin — a large protein essential for the function and maintenance of photoreceptor cells in the retina and hair cells in the inner ear. Patients typically have moderate-to-severe hearing loss from birth and develop progressive vision loss beginning in adolescence or early adulthood, often leading to legal blindness.
The USH2A gene is one of the largest genes in the human genome, with 72 exons encoding a protein of over 5,000 amino acids. Many pathogenic mutations are found in or around exon 13, which is the most commonly mutated region. Mutations that disrupt the reading frame in this region prevent production of functional usherin protein.
Exon skipping offers a therapeutic strategy for USH2A mutations in the exon 13 region. By designing an ASO to skip exon 13 during pre-mRNA splicing, the reading frame can be restored, producing a shorter but partially functional usherin protein. Preclinical studies have shown that usherin lacking the exon 13-encoded domain retains partial function — enough to support photoreceptor cell survival and slow retinal degeneration.
ProQR Therapeutics (now part of Lilly) developed QR-421a (Ultevursen), an ASO designed to skip exon 13 in USH2A pre-mRNA. QR-421a is administered by intravitreal injection directly into the eye. It is in Phase 2/3 clinical trials (the Sirius and Celeste studies) for patients with retinitis pigmentosa due to USH2A mutations affecting exon 13. Intravitreal delivery is advantageous because it achieves high local concentrations in the retina while minimizing systemic exposure.
The exon-skipping approach for USH2A shares the same scientific principle as the approved DMD exon-skipping drugs (Eteplirsen, Golodirsen, Casimersen, Viltolarsen): by removing an exon that contains a mutation disrupting the reading frame, the cell can produce a truncated but partially functional protein. The key difference is the target tissue — retinal cells rather than muscle cells — and the delivery route — intravitreal injection rather than intravenous infusion.
While QR-421a specifically targets exon 13 skipping, patients with USH2A mutations outside the exon 13 region may require different exon-skipping strategies. Pequliar designs personalized exon-skipping ASO candidates for any USH2A mutation, identifying the optimal exon to skip to restore the reading frame, designing antisense sequences for efficient skipping, and providing synthesis-ready sequences with full chemistry assignment and off-target screening.
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Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.