Antisense oligonucleotides targeting exon 11 are able to partially rescue the NF2-related schwannomatosis phenotype in vitro

NF2-related schwannomatosis (NF2-related SWN) is an autosomal dominant condition caused by loss of function variants in the gene, which codes for the protein Merlin and is characterized by the development of multiple tumors of the nervous system. The clinical presentation of the disease is variable and related to the type of the inherited germline variant. Here, we tested if phosphorodiamidate morpholino oligomers (PMOs) could be used to correct the splice signaling caused by variants at ±13 within the intron-exon boundary region and showed that the PMOs designed for these variants do not constitute a therapeutic approach. Furthermore, we evaluated the use of PMOs to decrease the severity of the effects of truncating variants with the aim of generating milder hypomorphic isoforms through the induction of the in-frame deletion of the exon-carrying variant. We were able to specifically induce the skipping of exons 4, 8, and 11 maintaining the gene reading frame at cDNA level. Only the skipping of exon 11 produced a hypomorphic Merlin (Merlin-e11), which is able to partially rescue the observed phenotype in primary fibroblast cultures from NF2-related SWN patients, being encouraging for the treatment of patients harboring truncating variants located in exon 11.