From hype to hope: foundational requirements for NF1 gene therapy success

Abstract

Gene therapy for Neurofibromatosis type 1 (NF1), defined as a collection of approaches that restore the quantity and function of neurofibromin, holds promise for treating various NF-associated clinical manifestations by addressing the root cause of the condition. The Gilbert Family Foundation’s Gene Therapy Initiative (GTI) launched one of the first focused research efforts to support a broad array of gene replacement, gene editing, and other strategies aimed at upregulating neurofibromin levels to mitigate symptoms and advance therapies for NF1. Efforts to discover and evaluate novel gene therapies to treat NF1 are hindered by foundational gaps in the field, the absence of quantitative assays, and a lack of robust preclinical models with reliable functional readouts. This perspective begins by shedding light on those key barriers that continue to hinder progress in NF1 gene therapy, outlines some of the strategies being explored to overcome them and offers pointers to additional strategies that merit further exploration. We then highlight several promising gene therapy strategies now in development. Successfully addressing the challenges described earlier is critical to realizing the full potential of these emerging and novel therapeutic approaches, setting the stage for effective and durable NF1 gene therapy interventions.

Keywords

Neurofibromatosis type 1 / gene therapy / neurofibromin

References

[1] Staedtke V,Bedwell D.Gene-targeted therapy for neurofibromatosis and schwannomatosis: the path to clinical trials.Clin Trials2024;21:51-66

[2] Peduto C,Nigro V,Piluso G.Neurofibromatosis type 1: pediatric aspects and review of genotype-phenotype correlations.Cancers2023;15:1217 PMCID:PMC9954221

[3] Yang FC,Chen S.Nf1-dependent tumors require a microenvironment containing Nf1^+/-- and c-kit-dependent bone marrow.Cell2008;135:437-48

[4] Joseph NM,Buchstaller J.The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells.Cancer Cell2008;13:129-40 PMCID:PMC2566828

[5] Le LQ,Shipman T,Suter U.Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development.Cancer Res2011;71:4686-95 PMCID:PMC3145496

[6] Kershner LJ,Wu J.Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment.JCI Insight2022;7 PMCID:PMC9675562

[7] Bostanthirige DH,Vatasescu JPS. Proof-of-principle of NF1 Gene Therapy in plexiform neurofibroma mice models. bioRxiv 2025;bioRxiv 2025.01.21.634081. Available from: https://www.biorxiv.org/content/10.1101/2025.01.21.634081v1.abstract [accessed 12 August 2025].

[8] Goto-Silva L.Single-cell proteomics: a treasure trove in neurobiology.Biochim Biophys Acta Proteins Proteom2021;1869:140658

[9] Wu J,Rizvi TA.Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells.Cancer Cell2008;13:105-16 PMCID:PMC2846699

[10] Jessen WJ,Jousma E.MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.J Clin Invest2013;123:340-7

[11] Zhu Y,Charnay P,Parada LF.Neurofibromas in NF1: Schwann cell origin and role of tumor environment.Science2002;296:920-2 PMCID:PMC3024710

[12] Kim J,Knoblich JA.Human organoids: model systems for human biology and medicine.Nat Rev Mol Cell Biol2020;21:571-84 PMCID:PMC7339799

[13] Gilbert Family Foundation Contributes nearly $375 million in partnership with Henry Ford Health to Bring Shirley Ryan AbilityLab to Detroit and create the Nick Gilbert Neurofibromatosis Research Institute. Available from: https://gilbertfamilyfoundation.org/news-and-stories/henry-ford-health-shirley-ryan-ability-lab-nick-gilbert-neurofibromatosis-institute/ [accessed 12 August 2025].

[14] Dombi E,Marcus LJ.Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas.N Engl J Med2016;375:2550-60

[15] Gross AM,Wolters PL.Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.Neuro Oncol2023;25:1883-94 PMCID:PMC10547508

[16] Li L.Disproportionate adverse event signals of selumetinib in neurofibromatosis type I: insights from FAERS.Front Pharmacol2024;15:1454418 PMCID:PMC11747384

[17] Chen AP,Wolters PL.KOMET study investigatorsEfficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study.Lancet2025;405:2217-30

[18] Moertel CL,Shuhaiber HH.for the ReNeu Study GroupReNeu: a pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN).JCO2024;42:3016-3016

[19] Leier A,Chen AT.Mutation-directed therapeutics for neurofibromatosis type I.Mol Ther Nucleic Acids2020;20:739-53 PMCID:PMC7225739

[20] Wang D,Gao G.Adeno-associated virus vector as a platform for gene therapy delivery.Nat Rev Drug Discov2019;18:358-78 PMCID:PMC6927556

[21] Raposo G.Extracellular vesicles: exosomes, microvesicles, and friends.J Cell Biol2013;200:373-83 PMCID:PMC3575529

[22] Tang SN,Heimann MK.Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain.Biomaterials2024;308:122562 PMCID:PMC11164054

[23] Salazar-Puerta AI,Cuellar-Gaviria TZ.Engineered extracellular vesicles derived from dermal fibroblasts attenuate inflammation in a murine model of acute lung injury.Adv Mater2023;35:e2210579 PMCID:PMC10573710

[24] Rincon-Benavides MA, Cuellar-Gaviria T, Alzate-Correa D, et al. Engineered extracellular vesicles as a therapeutic strategy for neurofibromatosis type I. Biomedical Engineering Society (BMES) Annual Meeting; 2023 Oct 11-14; Seattle WA. Available from https://2023bmesannual.eventscribe.net/fsPopup.asp?efp=Sk9RVlVJUUwyMDI3Nw&PresentationID=1315447&rnd=0.4760429&mode=presInfo [accessed 26 August 2025].

[25] Rincon-Benavides MA, Cuellar-Gaviria T, Alzate-Correa D, Powell H, Gallego-Pérez D, Higuita-Castro N. Designed extracellular vesicles loaded with NF1 nucleic acid as a novel therapeutic strategy for neurofibromatosis type 1. International Nanomedicine and Drug Delivery Symposium (NanoDDS); 2024 Sep 13-15; Orlando, FL.

[26] Ortega-Pineda L,Salazar-Puerta AI.Designer extracellular vesicles modulate pro-neuronal cell responses and improve intracranial retention.Adv Healthc Mater2022;11:e2100805

[27] Sun L,Du F,Chen ZJ.Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Science2013;339:786-91 PMCID:PMC3863629

[28] Chen X,Xie Y.A lupus-derived autoantibody that binds to intracellular RNA activates cGAS-mediated tumor immunity and can deliver RNA into cells.Sci Signal2025;18:eadk3320 PMCID:PMC12076517

[29] NF2BioSolutions. Available from https://nf2biosolutions.org/non-viral-gene-delivery-zhou-lab-at-yale-university/ [accessed 12 August 2025].

[30] Sharma J,Wong E.A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.Nat Commun2021;12:4358 PMCID:PMC8285393

[31] Osum SH,Corbière SMAS.Combining nonsense mutation suppression therapy with nonsense-mediated decay inhibition in neurofibromatosis type 1.Mol Ther Nucleic Acids2023;33:227-39 PMCID:PMC10384610

[32] Exploring Nonsense Suppression as a Treatment for NF1. Synapse: syn2164183.

[33] Takeda S,Hoffman EP.Exon-Skipping in Duchenne Muscular Dystrophy.J Neuromuscul Dis2021;8:S343-58 PMCID:PMC8673534

[34] McCauley ME.Antisense drugs for rare and ultra-rare genetic neurological diseases.Neuron2023;111:2465-8

[35] Leier A,Liu H.Targeted exon skipping of NF1 exon 17 as a therapeutic for neurofibromatosis type I.Mol Ther Nucleic Acids2022;28:261-78 PMCID:PMC8983316

[36] Church C. Targeted Exon Skipping of NF1 Exon 52 as a Mutation-Specific Therapeutic for Neurofibromatosis Type 1. 2024 Global NF Conference; 2024 Jun 20-25; Brussels, Belgium. Available from https://www.ctf.org/wp-content/uploads/2024/06/24_NFConferenceAbstractBook_web.pdf [accessed 26 August 2025].

[37] Lehtonen A,Trump D.Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence.Dev Med Child Neurol2013;55:111-25

[38] Botero V.Unraveling neuronal and metabolic alterations in neurofibromatosis type 1.J Neurodev Disord2024;16:49 PMCID:PMC11365184

[39] Kim TY,Rossman KL.Substrate trapping proteomics reveals targets of the βTrCP2/FBXW11 ubiquitin ligase.Mol Cell Biol2015;35:167-81

[40] Kohn DB,Spencer MJ.Successes and challenges in clinical gene therapy.Gene Ther2023;30:738-46 PMCID:PMC10678346

[41] Gao J,Xia ZJ.Gene therapy for CNS disorders: modalities, delivery and translational challenges.Nat Rev Neurosci2024;25:553-72