The 3849+10 kb C->T mutation is categorized as a Class V mutation (leading to reduced amounts of CFTR proteins at the cell surface). The 3849+10 kb C->T mutation leads to a specific splicing defect in the CFTR, resulting in the inclusion of 84 intronic nucleotides as a cryptic exon in the CFTR RNA. This cryptic exon contains a premature stop codon, leading to the degradation of a significant fraction of the RNA by the Nonsense mediated mRNA decay )NMD( mechanism, as well as to the production of truncated non-functional CFTR protein.
Although CFTR modulators are approved for patients carrying the 3849 mutation in US, their effect is very minimal. In EU, due to the lack of efficacy, no CFTR modulator drugs are approved for those specific patients. Therefore, a treatment with higher efficacy is needed for patients carrying the 3849 mutation.
Our ASO SPL84, delivered via inhalation, effectively penetrates the target cells in the lungs, and specifically binds to the target region, thereby preventing the inclusion of 84 intronic nucleotides as a cryptic exon, and generating a fully functioning CFTR protein.
Phase 1 was successfully completed; Phase 2 for 3849 unmet CF patients is targeted for H1 2024