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.
There are ~1500 patients carrying at least one 3849 allele, listed in the US Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) patient registries. In various populations the mutation is widespread, such as Jewish patients from Ashkenazi (Eastern European) descent, and populations in Slovenia, Poland and Italy.
Although CFTR modulators are approved for patients carrying the 3849 mutation in US, their effect is very minimal. 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 binds to the target region, thereby preventing the inclusion of 84 intronic nucleotides as a cryptic exon, and generating a fully functioning CFTR protein.
The program is in advanced stages, aiming for phase 1/2 clinical study initiation in 2022.