In vitro development of a new personalized therapy for patients with neurofibromatosis type 2

- Research

The Clinical Genomics group of the IGTP and the Genetics Service of the HUGTiP, members of the Spanish (CSUR) and European (ERN Genturis) reference centre in neurofibromatosis and related syndromes (Phakomatosis), have developed a new possible gene therapy in vitro for patients with genetic variants associated with a severe phenotype located in exon 11 of the NF2 gene as proof of concept. This therapeutic approach has been carried out thanks to the contribution of different associations of patients with neurofibromatosis (AcNefi, AANF, Chromo22) and competitive research projects (La Marató de TV3 -126/C/2020-, the Instituto de Salud Carlos III -PI20/00215-, Fundación Proyecto NF and the Children's Tumor Foundation -CTF-2019-05-005-). It is based on the use of molecules called antisense oligonucleotides with which it is possible to remove exon 11, carrier of the genetic variant that causes neurofibromatosis type 2, from the protein that encodes the NF2 gene, the merlin. This way, a new merlin protein is generated, capable of partially recovering the cellular structure presented by the skin cells of two patients, as well as reducing their ability to proliferate.

This work is a first evidence of the potential use of antisense therapy as a personalized therapy for patients with this genetic disorder of the nervous system in order to reduce the number of tumours they might develop in their lifetime. Specifically, for patients who contain genetic variants associated with a severe phenotype and located in exon 11 of the NF2 gene. However, "The function of this new form of merlin will need to be better characterized before we consider it for further animal or preclinical trials, and continue doing research to find a real cure for these patients and prevent disease progression" explains Dr Elisabeth Castellanos, coordinator of the Clinical Genomics Unit of the Northern Metropolitan Clinical Laboratory (LCMN) of the HUGTiP and associate researcher of the IGTP.

Neurofibromatosis type 2 is a devastating genetic condition, characterized by the development of multiple tumours of the nervous system for which there is a need to develop effective therapeutic options without adverse consequences. The clinical presentation of the disease is highly variable and is related to the type of genetic variant present in all the patient's cells.

Figure 5: Design and testing PMOs for NF2 splicing variants


Catasús N, Rosas I, Bonache S, Negro A, Torres-Martin M, Plana-Pla A, Salvador H, Serra E, Blanco I, Castellanos E; NF2-related SWN Spanish National Reference Centre HUGTP-ICO-IGTP. Antisense oligonucleotides targeting exon 11 are able to partially rescue the NF2-related schwannomatosis phenotype in vitro. Mol Ther Nucleic Acids. 2022 Nov 4;30:493-505. DOI: 10.1016/j.omtn.2022.10.026. PMID: 36420221; PMCID: PMC9678674.