None approved; Sepofarsen in Phase 2/3
Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy caused by mutations in the CEP290 gene, which encodes a centrosomal protein essential for the function of primary cilia. In the retina, cilia are critical for photoreceptor cell structure and the transport of molecules necessary for vision. Loss of CEP290 function leads to photoreceptor degeneration and severe visual impairment, typically from birth or early infancy.
The most common CEP290 mutation causing LCA10 is an intronic mutation (c.2991+1655A>G) in intron 26. This deep intronic point mutation creates a novel splice donor site, causing the inclusion of a 128-nucleotide pseudoexon (a segment of intronic DNA that is aberrantly recognized as an exon) in the CEP290 mRNA. The pseudoexon introduces a premature stop codon, leading to nonsense-mediated mRNA decay and loss of CEP290 protein. This mutation accounts for the majority of LCA10 cases.
This disease mechanism is an ideal target for a specific ASO strategy: pseudoexon blocking. An ASO designed to bind the cryptic splice site created by the mutation prevents the splicing machinery from recognizing the pseudoexon. With the pseudoexon excluded, normal CEP290 mRNA is produced, and functional CEP290 protein is restored. The ASO does not correct the DNA mutation — it simply prevents the mutation from affecting mRNA splicing.
ProQR Therapeutics developed Sepofarsen (QR-110), an ASO designed to block the pseudoexon caused by the c.2991+1655A>G mutation in CEP290. Sepofarsen is administered by intravitreal injection into the eye. Phase 1/2 clinical data showed improvements in retinal sensitivity and visual function in some patients, with an acceptable safety profile. The drug is in Phase 2/3 trials.
LCA10 and Sepofarsen represent an important proof of concept for pseudoexon-blocking ASOs. Deep intronic mutations that create cryptic splice sites are increasingly recognized as a significant category of pathogenic variants across many genes, often missed by standard genetic testing that focuses on exonic regions. Whole-genome sequencing is revealing more of these mutations, and ASOs are uniquely suited to address them because they can target intronic sequences that are only transiently present in the pre-mRNA.
Pequliar designs pseudoexon-blocking ASO candidates for CEP290 mutations and other deep intronic mutations that create cryptic splice sites. The platform identifies the aberrant splice site, designs antisense sequences to block its recognition by the spliceosome, and scores candidates for binding affinity, structural accessibility, and off-target safety. Synthesis-ready sequences with full chemistry assignment are provided for preclinical evaluation or compassionate use applications.
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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.