Publication:
Investigating therapeutic nonsense suppression in a neurofibromatosis mouse model

dc.contributor.coauthorWu, Chan
dc.contributor.coauthorShazeeb, Mohammed Salman
dc.contributor.coauthorMangkalaphiban, Kotchaphorn
dc.contributor.coauthorHan, George
dc.contributor.coauthorRentiya, Zubir S.
dc.contributor.coauthorGounis, Matthew J.
dc.contributor.coauthorJacobson, Allan
dc.contributor.kuauthorPeker, Ahmet
dc.contributor.unitKoç University Hospital
dc.date.accessioned2024-12-29T09:37:25Z
dc.date.issued2024
dc.description.abstractNeurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.
dc.description.indexedbyWoS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.publisherscopeInternational
dc.description.sponsorsThis work was supported by grants to A.J. (616394) and to M.J.G. and Miguel Esteves (563749) from the Gilbert Family Foundation. We thank: PTC Therapeutics Inc. for providing ataluren and for facilitating access to ataluren infused chows; the UMass Chan Image Processing and Analysis Core (iPAC) for computing resources; Marla Weetall and Xin Zhao for helpful discussions; Viraj Moholkar and Aditya Joshi for their help with image analyses; and Drs. Robert King and Shaokuan Zheng (Advanced MRI Center at UMass Chan) for their technical support with the imaging experiments.
dc.description.volume380
dc.identifier.doi10.1016/j.expneurol.2024.114914
dc.identifier.eissn1090-2430
dc.identifier.issn0014-4886
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85200926931
dc.identifier.urihttps://doi.org/10.1016/j.expneurol.2024.114914
dc.identifier.urihttps://hdl.handle.net/20.500.14288/22369
dc.identifier.wos1295660700001
dc.keywordsAtaluren
dc.keywordsNeurofibromatosis
dc.keywordsPlexiform neurofibromas
dc.keywordsPatient-derived Nf1 mouse model
dc.keywordsSex factors in NF1
dc.languageen
dc.publisherACADEMIC PRESS INC ELSEVIER SCIENCE
dc.sourceExperimental Neurology
dc.subjectNeurosciences
dc.titleInvestigating therapeutic nonsense suppression in a neurofibromatosis mouse model
dc.typeJournal article
dspace.entity.typePublication
local.contributor.kuauthorPeker, Ahmet

Files