NF2 lacking exon 11 induced by antisense gene therapy is able to partially recover merlin deficiency in NF2-SWN...

NF2-related schwannomatosis (NF2-SWN) is an inherited autosomal dominant disorder resulting from loss-of-function mutations in the NF2 gene, for which no effective treatment is currently available. Furthermore, truncating variants in NF2 are associated with the severest phenotype compared to in-frame or missense variants. Previously, a shorter NF2 isoform with exon 11 skipped (merlin_e-11), induced through antisense phosphorodiamidate morpholino oligomers (PMOs), was able to partially rescue the deleterious effect of nonsense variants located at that exon in patients' primary fibroblasts. To test the potential of this approach in Schwann cells, the NF2-SWN tumorigenic cells, we developed an induced pluripotent stem cell (iPSC)-based model carrying heterozygous and homozygous truncating variants in NF2 exon 11 and differentiated them into Schwann cell-forming spheroids. After 3 days of treatment, merlin_e-11 expression was induced in NF2-deficient cell lines. Furthermore, key pathways associated with NF2-deficiency in schwannomas, such as PI3K/Akt/mTORC and YAP levels, were recovered without signs of toxicity. These results confirm that the PMO treatment induces effective skipping of exon 11 in Schwann cell spheroids, generating a hypomorphic merlin_e-11 that has the capacity to partially rescue merlin-deficiency in an NF2-SWN spheroid cell model and that it is a potential treatment of patients who harbor truncating variants located in exon 11.