The W1282X mutation generates a Premature Termination Codon (PTC), leading to RNA degradation induced by the Nonsense Mediated RNA Decay (NMD) mechanism.
Around 1600 patients carry this mutation listed in the US Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) patient registries.
W1282X does not respond to CFTR modulator drugs. Heterozygous patients carrying the F508del mutation and a minimal function mutation are responsive to Vertex triple combination therapy (Trikafta®). Significantly, around 50% of CF patients carrying W1282X also carry a non-F508del mutation on the second allele. For those patients, no effective treatment is available.
SPL23-2 ASO given by inhalation, penetrates the cells and skips over exon 23 in the CFTR transcript. Skipping exon 23 bypasses the NMD of transcripts carrying W1282X leading to mature and active CFTR. The activity of these CFTR channels can be further augmented by CFTR modulators.