RARE DISEASE
Neurofibromatosis type 1
Neurofibromatosis type 1
Neurofibromatosis type 1
Synonyms: Nonmosaic NF1, Nonmosaic neurofibromatosis type 1, Von Recklinghausen disease
Synonyms: Nonmosaic NF1, Nonmosaic neurofibromatosis type 1, Von Recklinghausen disease
Synonyms: Nonmosaic NF1, Nonmosaic neurofibromatosis type 1, Von Recklinghausen disease
Drug discovery
10
drugs
With orphan designations
Overview
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by NF1 gene mutations, leading to dysregulated Ras signaling and tumor suppressor loss. It manifests with café-au-lait macules, neurofibromas, Lisch nodules, and skeletal anomalies. Complications include plexiform neurofibromas (30-50% of cases), optic gliomas, malignancy risks (e.g., MPNST), and neurocognitive deficits. Diagnosis requires ≥2 NIH criteria (e.g., ≥6 café-au-lait spots, axillary freckling, or optic pathway glioma) [1][6][16].
Burden
Physical: Chronic pain (42% require analgesics), disfigurement, and MPNST risk (8-13%) [4][9][14].
Psychosocial: 50-75% experience learning disabilities; 32% employment rate despite education [4][12][14].
Economic: Lifelong surveillance (MRI, specialists) and ~23% report poor/fair physical health [4][9][12].
Therapies
MEK inhibitors (e.g., selumetinib) for symptomatic, inoperable plexiform neurofibromas [5][8][18].
Surgery for tumor debulking or malignancy; multidisciplinary care for neurocognitive, orthopedic, and ocular complications [3][5][16].
Emerging therapies: Gene therapy (AAV vectors) and dual-pathway inhibitors targeting Ras/cAMP in clinical trials [8][13][18].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,937 drug discovery papers about Neurofibromatosis type 1, with 1 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,937 drug discovery papers about Neurofibromatosis type 1, with 1 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-05-18 | Large-Scale Assessment of NF1 Single Amino Acid Variants as HLA Class I Neoantigens.
Neoantigens are cancer-specific antigens arising from genomic alterations. Single Amino Acid Variants (SAAVs) represent a primary class of these neoantigens. To evaluate the therapeutic potential of Neurofibromin 1 (NF1)-derived SAAVs - given that NF1 is frequently mutated in malignant brain tumors - we prioritized the 40 NF1 SAAVs determined to be HLA-A*02:01 binders using computational prediction coupled with experimental validation. To validate these predicted neoepitopes, we employed a two-tiered experimental approach in HLA-A*02:01 homozygous U87-MG cells. We first synthesized minigene constructs encoding the predicted neoepitopes, introduced them via lentiviral transfection and confirmed their expression by mass spectrometry (MS). Subsequently, we performed endogenous validation using pan-HLA immunoprecipitation mass spectrometry (IP-MS), confirming 4 (10 neoepitopes) of the 40 candidate SAAVs. We observed a discrepancy between in silico predictions and the observed sequences. Our endogenous peptidomics further revealed conserved peptide motifs and demonstrated that peptide selection for HLA presentation is transient. While our study substantiates the therapeutic feasibility of T-cell immunotherapies targeting NF1 mutations, these results underscore a limitation in current computational prediction. Our study highlights the necessity of experimental validation to refine neoantigen prioritization strategies.
2026-04-02 | Identification of CD74-positive antigen presenting glioma cells in primary human tumors and murine models of NF1 high-grade glioma.
Compared to the general population, individuals with Neurofibromatosis Type 1 have a 50-fold higher risk of developing a high-grade glioma (HGG) in their lifetime. Despite improved understanding of the molecular and cellular drivers of these neoplasms, we have yet to translate this knowledge into therapies that improve overall survival. One limitation has been the paucity of in vivo models for drug testing within this population. We generated 3 distinct glioma stem cell lines from high-grade gliomas arising in mice with Nf1 and Trp53 mutations in cis (NPcis) and characterized the allografts resulting from one Nf1-glioma stem cell line (Nf1-HGG17) by single cell and single nuclear RNA-seq. Because our cell lines are grown in stem cell media, there is an inherent reduction of the differentiation states present in primary HGG, with only oligodendrocyte precursor-like and neural-like cells identified. However, orthotopic allografts of Nf1-HGG17 regained the other differentiation states typically observed in HGG and GBM (neuronal progenitor cell-like and astrocyte-like). About half of neoplastic cells cluster separately from these classical groups and highly express genes of the antigen presentation machinery, including Cd74, which we also observed in patient samples. Notably, heterozygosity of Nf1 within the tumor microenvironment does not cause marked changes in the immune tumor microenvironment, gene expression, or differentiation states of neoplastic cells. These data indicate that allografted HGG lines from NPcis mice are an effective model of NF1-HGG, mimicking the complexity observed in human HGG, that can be used for larger scale in vivo drug screening and evaluation.
2026-01-17 | Asthma-mediated control of optic glioma growth via T cell-microglia interactions: A mathematical model.
Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. A connection between asthma and optic glioma has previously been observed, but the mechanisms are unclear. To elucidate the role of asthma in the regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in the regulation of microglia, a key player in the glioma tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that inflammation can play a key role in suppressing the proliferation of optic glioma cells via immune reprogramming of T cells and the delicate control of signaling networks in microglia. Our mathematical model unveils the complex interactions between tumor and immune cells in optic glioma. Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.
2025-09-22 | Circumferentially Exposed Achilles Tendon Wound Reconstruction Using Free Anterolateral Thigh Flap With Vascularized Fascia Lata Wrapping.
Resection of a giant plexiform fibroma on the lower leg of a 75-year-old woman with neurofibromatosis type 1 resulted in an extensive skin soft tissue defect and a circumferentially exposed wound involving the Achilles tendon. As secondary reconstruction was performed after a waiting period to rule out a malignant peripheral nerve sheath tumor using histopathological examination, the major challenge was to prevent adhesion of the Achilles tendon to the surrounding granulation tissue, in addition to reconstructing the extensive skin soft tissue defect. We overcame this problem by using a free anterolateral thigh flap with the vascularized fascia lata wrapping technique. A free composite anterolateral thigh flap with fascia lata is a recognized method for primary reconstruction of the Achilles tendon and overlying soft tissue defects. We selected this method not for reconstruction of the Achilles tendon defect, but to prevent adhesion of the tendon to the surrounding tissue. The exposed Achilles tendon was circumferentially wrapped with vascular fascia lata. The postoperative range of motion of the ankle joint was 5 degrees in dorsiflexion and 45 degrees in plantar flexion. Although dorsiflexion was impaired, the patient was able to walk unassisted and had no problems in daily life. The appearance around the ankle joint was good. We report the novel use of a free anterolateral thigh flap with vascularized fascia lata in periapical Achilles tendon reconstruction.
2025-09-02 | Evaluating CAR-T cells from neurofibromatosis type 1 (NF1) patients for targeting AXL in malignant peripheral nerve sheath tumors associated with NF1.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by neurofibromas, with 5-13% of patients risk developing malignant peripheral nerve sheath tumors (MPNST). Current treatments for MPNST are largely ineffective. AXL, overexpressed in MPNST, is a potential target for Chimeric Antigen Receptor T (CAR-T) cell therapy. This study evaluates the immunophenotypes, efficacy, and safety of NF1-derived AXL-CAR-T cells in treating MPNST. AXL-CAR-T cells, containing an anti-AXL single-chain variable fragment, were derived from NF1 patients (n = 27) and healthy donors (n = 15). Immunophenotypes were characterized using CCR7, CD45RA, CD4, and CD8 markers. The cytotoxicity of CAR-T cells was tested in vitro against MPNST cells, and efficacy and safety were evaluated in an MPNST xenograft mouse model. Multiplex immunoassays and ELISA measured cytokines and granzyme b release. AXL-CAR-T cells from both NF1 patients and healthy donors had a similar partition in stem cell-like memory T cell composition and comparable ex vivo expansion. AXL-CAR-T cells from both groups effectively lysed MPNST cells in vitro. In vivo, tumor volumes in xenograft mice were significantly reduced with no on-target off-tumor toxicity. NF1 patient-derived AXL-CAR-T cells demonstrated similar quality and efficacy to those from healthy donors, supporting their potential autologous therapy for MPNST.
small molecules
2026-08-11 | Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors.
Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.
2026-08-05 | DNA Hypomethylation Is Not Cell Intrinsically Toxic to Polycomb Repressive Complex 2 Deficient Malignant Peripheral Nerve Sheath Tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for neurofibromatosis type 1 (NF1) patients. In the context of NF1, MPNSTs develop from benign premalignant precursors and the transition to malignancy is typically accompanied by loss of the polycomb repressive complex 2 (PRC2), which results in aberrant upregulation of over 1200 genes due to global depletion of histone H3 lysine 27 trimethylation (H3K27me3). Previous studies suggest cells compensate for the loss of this repressive histone mark via hypermethylation of the genome. Here we analyzed genome-wide DNA methylation and the transcriptome in MPNST cell lines and isogenic PRC2-deficient and -proficient CRISPR-engineered immortalized human Schwann cells. In addition to effects of PRC2 status, we also measured the effects of two DNA methyltransferase inhibitors (DNMTi), decitabine and azacitidine. We found that PRC2 status does not affect global DNA methylation or average methylation levels across specific genomic features. Furthermore, decitabine and azacitidine have differential effects on MPNSTs. While both DNMTis hypomethylate the genome, they upregulate different targets. Azacitidine upregulates genes involved in RNA processing pathways and exhibits direct tumor cell cytotoxicity, while decitabine upregulates genes involved in the immune response, has no direct-cell killing effects, and likely suppresses tumor growth in vivo by altering the tumor microenvironment. We show that DNA hypomethylation alone is insufficient to kill MPNST cells, regardless of PRC2 status. Consequently, these findings suggest that DNMT inhibitors should be utilized in combination with other targeted therapies for MPNST patients.
2026-08-02 | Case Report: Schwann cell reprogramming and PDGF-driven nerve hypertrophy in an NF1 patient with CIDP-like autoimmunity.
Differentiating neoplastic proliferation from inflammatory fibrosis in peripheral nerve hypertrophy is critical. We report a patient with a neurofibromatosis type 1 (NF1) deletion exhibiting extreme diffuse nerve enlargement and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like autoimmunity. This study aims to elucidate the underlying endoneurial fibrotic mechanism, specifically focusing on the signaling networks between Schwann cells (SCs) and fibroblasts. Single-cell RNA sequencing was performed on a biopsied sural nerve to profile the cellular and transcriptomic landscape. Intercellular interactome and pseudotime trajectory analyses were utilized to map molecular evolution and signaling crosstalk. Transcriptomic profiling revealed that SCs-which normally maintain myelin around axons and support peripheral nerve function-were pathologically entrapped in a dedifferentiated state. Serving as a genetic primer, the NF1 deletion lowered the threshold for SC reprogramming, a vulnerability that was subsequently unleashed by a severe autoimmune infiltrate consisting of macrophages and T cells. These reprogrammed SCs abandoned myelin-maintaining genes, such as MPZ, to acquire a pro-fibrotic phenotype. Through a coordinated platelet-derived growth factor (PDGF) dual-axis network involving PDGFC-PDGFRA and PDGFD-PDGFRB, the entrapped SCs exclusively secreted PDGF ligands that potently activated endoneurial fibroblasts and vascular mural cells. This persistent paracrine signaling orchestrated excessive extracellular matrix deposition, driving a massive expansion of the endoneurial interstitium and the formation of classic "onion bulbs". Our data suggest that the macroscopic hypertrophic changes observed in this specific clinical presentation may reflect an aberrant, immune-triggered fibrotic cascade-where autoimmune leukocyte infiltration continuously drives stromal overgrowth-complementing rather than entirely precluding the classical RAS/MAPK-driven neoplastic SC hyperproliferation. Furthermore, within the limitations of this pilot evaluation, characterizing this potential SC-fibroblast crosstalk indicates that the PDGF signaling pathway may warrant further investigation as a candidate translational therapeutic target for refractory hypertrophic neuropathies.
2026-07-27 | A standardized imaging and analysis workflow for quantitative evaluation of cutaneous neurofibromas in Nf1-KO mice.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder in which cutaneous neurofibromas (cNFs) represent one of the most common and burdensome manifestations. No approved pharmacological treatment exists. Preclinical studies are essential to evaluate candidate therapies, but reliable outcome and endpoint measures for cNFs in animal models remain limited. We developed and validated a standardized methodology to assess drug efficacy in the Prss56Cre Nf1-KO mouse model which recapitulates key features of cNFs. In this model, Nf1 inactivation and tdTomato (Tom) reporter expression were specifically targeted to Schwann cells (SCs) responsible for cNF development. This approach enables real-time monitoring, isolation, and manipulation of tumor SCs at any time. We defined macroscopic (tumor count, total Tom+ fluorescent surface area, fluorescence intensity) and microscopic (cell-type composition defined by immunolabeling with a panel of specific markers, area quantification) endpoints, developed dedicated ImageJ scripts for automated image analysis, and compared the results with those obtained using the conventional manual method. Both automated measurements showed excellent reproducibility (ICC = 1) and strong correlation with manual analysis (Spearman's coefficient > 0.90), while significantly reducing analysis time (up to 100-fold faster). Bland-Altman analyses confirmed the absence of systematic bias compared with manual scoring. The standardized image naming and metadata integration further facilitated data consolidation and statistical analysis. This validated approach provides a reliable, reproducible, and time-efficient framework for evaluating drug effects on cNFs in preclinical studies. It establishes a foundation for robust efficacy testing of candidate therapies, facilitates cross-study comparability, and accelerates therapeutic development and clinical translation.
2026-07-22 | Carboplatin induces optic nerve oligodendrocyte loss and impairs myelin sheath microstructure in a mouse model of neurofibromatosis type 1 (NF1).
Vision impairment is a significant concern for children with Neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). While carboplatin-containing chemotherapy is often first-line therapy for NF1-OPG, it does not consistently improve visual function. Furthermore, chemotherapy is associated with altered white matter microstructure in individuals with NF1-OPG, suggesting a detrimental effect on oligodendroglia. We analyzed the tumor-independent effects of carboplatin on oligodendrocytes in Nf1-mutant mice and evaluated pharmacological strategies for reducing this chemotherapy-associated toxicity. Carboplatin- or vehicle-treated Nf1+/- mice or Nf1-mutant optic glioma cells were employed to assess the effects of restorative interventions on optic nerve oligodendrocytes in vivo and tumor cell growth in vitro, respectively. Clinically relevant carboplatin dosing induced oligodendrocyte loss and impaired myelin sheath structure in the optic nerves of Nf1+/- mice, an effect not observed following vinca alkaloids or MEK inhibitor (selumetinib) treatment. Carboplatin downregulates genes essential for cholesterol biosynthesis and decreases cholesterol levels in carboplatin-exposed Nf1+/- optic nerves, such that dietary cholesterol supplementation after carboplatin exposure restored oligodendrocyte numbers. Carboplatin also increases the density of monocytes (microglia/macrophages) in the Nf1+/- optic nerves. Using PLX5622 (a CSF1R inhibitor) to reduce monocytes numbers or using clemastine to promote the generation and survival of oligodendrocytes, alleviated the oligodendrocyte loss caused by carboplatin treatment. Notably, PLX5622 and clemastine reduced the viability of Nf1-mutant optic glioma tumor cells. Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure.
proteins
2025-07-01 | Single-cell tumor microenvironment profiling informs a circulating proteome test for the interception of malignant transformation in NF1 nerve sheath tumors.
The most common cause of death in neurofibromatosis type 1 (NF1) is the development of malignant peripheral nerve sheath tumor (MPNST), a deadly sarcoma that can transform from benign plexiform neurofibromas (PN) or premalignant atypical neurofibromas (AN). We built a single-cell dataset of 55 NF1-associated PN, AN, and MPNST to define cellular changes in neurofibroma at-risk of malignant transformation. Integrative analysis of changes in the tumor microenvironment revealed the emergence of malignant tumor cells, regulatory T cells, and loss of activated macrophages in MPNST. Using this reference dataset, we validated findings using anchor-based label transfer in an additional 19 NF1 nerve sheath tumors profiled with single cell sequencing, and public datasets. We then defined protein biomarkers of malignant transformation from high-throughput proteomic analysis of plasma samples collected from 45 NF1 patients that correlated to mRNAs specific to MPNST cell populations. Fifty plasma proteins accurately and non-invasively distinguished patients with MPNST from those with premalignant tumors. These markers should improve the ability to identify high-risk neurofibromas for improved cancer surveillance and enable early detection of malignant transformation in NF1.
2024-09-14 | Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.
Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.
2024-08-22 | Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues.
The neurofibromatosis type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we performed spatial transcriptomics to define the molecular signatures occurring during normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-β, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1fl/- (Nf1Postn) fracture callus. Transcriptional analyses, subsequently confirmed through phospho-SMAD1/5/8 immunohistochemistry, demonstrated a lack of BMP pathway induction in Nf1Postn mice. To gain further insight into the human condition, we performed spatial transcriptomic analysis of fracture pseudarthrosis tissue from a patient with NF1. Analyses detected increased MAPK signaling at the fibrocartilaginous-osseus junction. Similar to that in the Nf1Postn fracture, BMP pathway activation was absent within the pseudarthrosis tissue. Our results demonstrate the feasibility of delineating the molecular and tissue-specific heterogeneity inherent in complex regenerative processes, such as fracture healing, and reconstructing phase transitions representing endochondral bone formation in vivo. Furthermore, our results provide in situ molecular evidence of impaired BMP signaling underlying NF1 pseudarthrosis, potentially informing the clinical relevance of off-label BMP2 as a therapeutic intervention.
2024-07-12 | The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.
2024-03-27 | Estrogen-induced glial IL-1β mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma.
Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1β (IL-1β), which is neurotoxic to RGCs in vitro. Importantly, both IL-1β neutralization and leuprolide-mediated estrogen suppression decrease IL-1β expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss.
antibodies
2026-05-04 | Immune landscape characterization of neurofibromas with atypical features in Neurofibromatosis1 reveals PD-1 and the Tim-3/Galectin-9 pathway as potential therapeutic targets.
Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to the development of plexiform neurofibromas (pNF), benign tumors of the nerve sheath that can progress to malignant peripheral nerve sheath tumors (MPNST). Some pNFs exhibit atypical characteristics, particularly atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), which meet recently defined criteria. These are pNFs with concerning histological and/or molecular features and uncertain behavior, leading to their consideration as potential precursors of MPNSTs. In this study, we characterized the immune landscape of a series of atypical neurofibromas (exhibiting increased cellularity or atypical cells) and ANNUBPs (ANF/ANNUBP) compared to cutaneous neurofibromas (cNF), pNFs, and MPNSTs, all from patients with NF1, using immunohistochemistry and single-cell RNA sequencing (scRNA-seq). Our findings revealed that ANF/ANNUBPs are heavily infiltrated with CD3+ T-lymphocytes and CD163+ macrophages. Transcriptomic profiling using the NanoString technology demonstrated that ANF/ANNUBPs exhibit a distinct immune signature compared to both pNFs and MPNSTs. This includes overexpression of two inhibitory immune checkpoints (ICs): HAVCR2 (encoding the IC receptor Tim-3) and its primary ligand Galectin-9 (Gal9). Subsequent analyses of scRNA datasets corroborated these findings with Prss56Cre/+, Nf1fl/fl, R26tdTom/+ mouse model-derived tumors. Using multiplex immunofluorescence, we showed that CD3+ T-cells express the inhibitory IC PD-1, while CD163+ macrophages express both Tim-3 and Gal9. Furthermore, tumor cells within ANF/ANNUBPs were positive for activated caspase-3, suggesting a possible role of the immune microenvironment in controlling tumor growth or inducing cell death. Through deep-targeted DNA sequencing, we detected loss of cell cycle regulators (especially CDKN2A) in ANF/ANNUBPs but no somatic alteration of polycomb repressor complex components EED and SUZ12, the latter typically associated with MPNSTs, even at low frequencies. Additionally, loss of H3K27me3 was associated with even lower densities of CD3+ T-cells and CD163+ macrophages in MPNSTs, and the loss of p16 seemed to act synergistically. Taken together, these findings suggest that an immune response involving both T-lymphocytes and macrophages may play a role in controlling or delaying the malignant transformation of ANF/ANNUBPs into MPNSTs and point to IC molecules as novel immunopreventive strategies in NF1 patients with ANF/ANNUBPs.
2026-04-10 | The Cell Surface Proteome of Malignant Peripheral Nerve Sheath Tumors Reveals Therapeutic Targets.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for Neurofibromatosis Type 1 (NF1) patients. In the context of NF1, MPSNTs develop from benign premalignant precursors. The transition to malignancy is usually accompanied by loss of the polycomb repressive complex 2 (PRC2), leading to aberrant upregulation of many genes. The specific mechanisms disrupted by PRC2 loss remain incompletely understood. There is a significant gap in our knowledge of which cell-surface targets become derepressed and therapeutically actionable following PRC2 loss, contributing to the current lack of effective targeted therapies for MPNSTs. This study aims to address this gap by using cell-surface capture technology with mass spectrometry to profile MPNST models. In doing so, we define PRC2-dependent effects on the cell surface proteome, including specific biological pathways that are enhanced or suppressed at the cell surface protein level. We also create an MPNST cell-surface protein compendium comprised of proteins that are highly expressed across a variety of well-defined MPNST models. We prioritized proteins that are preferentially expressed in MPNST or other cancers and for which FDA-approved therapies already exist. Specific proteins from this compendium were molecularly targeted with antibody-drug conjugates in these models to surmise their therapeutic efficacy. Results reveal PTK7 as a novel and promising target for MPNST. In total, these efforts represent a step toward addressing the knowledge gap in MPNST genesis and identifying new therapeutic targets for further testing. Additionally, this data serves as a resource for other researchers wishing to characterize specific molecular targets.
2026-03-02 | IFN signaling at the nexus of the radiotherapy response in malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that constitute a major cause of mortality in individuals with neurofibromatosis type 1 (NF-1) and exhibit highly variable responses to radiotherapy. In this issue of the JCI, Zhu and colleagues integrated functional genomics, single-cell transcriptomics, and analysis of human tumors to show that type I IFN signaling shapes both tumor-intrinsic radiation sensitivity of MPNSTs and local recruitment and activation of T cells. Their findings establish IFN signaling as a central coordinator of the radiotherapy response in MPNSTs and suggest that incorporating targeted immunomodulation strategies may improve radiotherapy outcomes. The work also has direct implications for the role of the immune system and IFN signaling radiation-based treatment of soft tissue sarcomas beyond those involved in NF-1.
2026-01-27 | FAP expression as a marker of malignant transformation enabling in vivo characterization in peripheral nerve sheath tumors: a multimodal and translational study.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and a major cause of mortality in neurofibromatosis type 1 (NF-1). Distinguishing MPNSTs from benign neurofibromas remains challenging. We investigated fibroblast activation protein alpha (FAP) as a malignancy biomarker and theranostic target in peripheral nerve sheath tumors. Therefore, we integrated publicly available bulk transcriptomics, spatial transcriptomics, and single-cell RNA sequencing with immunohistochemistry (IHC) on independent archival samples. We further directly assessed clinical translatability using FAP-targeted PET/CT in an NF-1 patient undergoing work-up for suspected malignant transformation. Across independent bulk datasets, FAP was consistently up-regulated in MPNSTs compared with neurofibromas. In the TCGA sarcoma dataset, FAP varied by histotype but was clearly expressed in MPNSTs. Spatial transcriptomics revealed enrichment of FAP-high regions in MPNSTs and co-localization with tumor cell markers. Single-cell analysis showed FAP expression in MPNST tumor cells and cancer-associated fibroblasts, with the highest levels in neural crest-like tumor subpopulations previously linked to adverse prognosis; pseudotime analysis indicated decreasing FAP expression along trajectories toward Schwann cell precursor-like states linking FAP expression to a more primitive, dedifferentiated tumor cell state. IHC confirmed strong, predominantly tumor cell-intrinsic FAP expression in MPNSTs, with minimal staining in neurofibromas and normal tissues. Plexiform neurofibromas exhibited intermediate FAP expression. In clinical imaging, FAP-PET demonstrated higher tracer uptake in histologically proven MPNSTs than in benign lesions within the same patient, including a neurofibroma that was FDG-avid but FAP-negative, supporting added diagnostic specificity over FDG-PET/CT. In summary, FAP is robustly overexpressed in MPNSTs at transcript and protein levels, potentially concentrates in high-risk tumor cell states, and is detectable by targeted PET imaging. These findings identify FAP as a clinically relevant biomarker for malignancy in NF-1-associated tumors and support implementation of FAP-directed diagnostics and therapeutics in peripheral nerve sheath tumor work-up.
2025-11-17 | A novel germline NF1 splicing variant drives the onset of an anorectal mucosal melanoma in a patient with a stable and durable nivolumab response.
Neurofibromatosis type-1 (NF1) patients rarely develop mucosal melanomas. We report a rare form of anorectal mucosal melanoma (ARMM) in an NF1 syndromic patient profiled for genomics and transcriptomics to assess the determinants of the response to nivolumab. Primary melanoma and metastases were analyzed with targeted sequencing and gene expression profile (tGEP). We applied in silico (cBioPortal and predictor tools) and in vitro (hybrid minigene) approaches to confirm the variant pathogenicity. We detected the novel c.4269+2_4269+3delTG germline splicing variant in NF1, which proved to be pathogenic by the minigene assay showing an aberrant splicing. The tumor showed a copy-number (CN) neutral loss of heterozygosity for the WT allele, and both ARMM and metastases carried several CN gains associated with NF1-driven carcinogenesis and very low mutation burden. The tGEP analysis unveiled a macrophagic infiltration, with a pro-inflammatory M1-type polarization, in the context of lack of PD-L1 expression. The response to nivolumab in a germline NF1-driven ARMM case seems independent from levels of TMB and PD-L1 expression and may be mediated by inflammatory response induced by M1-polarized macrophages.
other
2026-02-13 | Proof-of-principle of NF1 gene therapy in plexiform neurofibroma xenograft mouse models.
Neurofibromatosis type I is a rare neurocutaneous syndrome characterized by the development of disfiguring neurofibroma tumors with unmet clinical needs. As Neurofibromatosis Type I is a monogenic disease, the development of gene therapy is highly attractive, but it is currently unknown if rescuing the NF1 gene in established neurofibroma is sufficient for tumor regression. Here, we test this hypothesis by building two novel NF1 mouse models with reversible NF1 expression. In the first model, the human NF1 -/- Schwann cells named ipNF95.11b C/T are genetically modified with a doxycycline-inducible full-length mouse Nf1 gene. One month after cells implantation in the sciatic nerve, mice are split into two treatment groups and received either doxycycline or control water. Strikingly, most sciatic nerves from mice allowed to drink doxycycline water for one month do not display neurofibroma histologically (2 out of 16 sciatic nerves, 13%) whereas 75% (12 out of 16 sciatic nerves) develop or maintain a neurofibroma when drinking control water. In the second model, the human NF1 +/- Schwann cells named ipNF95.11 C are genetically modified with a doxycycline-inducible potent shRNA against the NF1 mRNA transcript. Strikingly, doxycycline withdrawal after neurofibroma establishment allowed limited neurofibroma maintenance (3 out of 14 sciatic nerves, 21%), whereas most sciatic nerves showed evidence of neurofibroma when kept on doxycycline (12 out of 14 sciatic nerves, 86%). Finally, intrathecal injection of the full-length Nf1 lentivirus in established 1-month ipNF95.11b C/T xenograft pNF significantly reduced tumor burden. All mice are female. Thus, we provide proof-of-principle of the efficacy of NF1 Gene Therapy in plexiform neurofibroma mice models, paving the way to the development of therapeutic gene therapy solutions for NF1 patients.
2026-02-13 | Neurofibromin 1 (NF1) Splicing Mutation c.61-2A>G: From Aberrant mRNA Processing to Therapeutic Implications In Silico.
The neurofibromin 1 (NF1) splice-site mutation c.61-2A>G (rs1131691100) is a rare, pathogenic, autosomal dominant variant that disrupts NF1 tumor-suppressor function, causing neurofibromatosis type 1 (NF1). Its pathogenic mechanism is poorly understood, and the potential for personalized therapeutic genome editing remains unknown due to the absence of a standard framework for investigating splicing disorders. Here, we performed a comprehensive multi-omics analysis of a de novo c.61-2A>G case from South Korea, integrating short- and long-read whole genome sequencing, whole transcriptome sequencing, and methylation profiling. We confirm that c.61-2A>G abolishes the canonical splice acceptor site, activating a cryptic splice acceptor 16 nucleotides downstream in exon 2. This splicing shift generates a 16-nucleotide deletion, causing a frameshift and premature stop codon that truncates the protein's N-terminal region. Long-read sequencing further reveals that the mutation creates a novel CpG dinucleotide, which is methylated in the majority of reads. Finally, we assessed therapeutic correction strategies, revealing that CRISPR-Cas9 prime editing is the only viable approach for in vivo correction. This study provides the first comprehensive multi-omics characterization of the NF1 c.61-2A>G mutation and establishes a minimal framework for precision therapeutic development in silico in monogenic splicing disorders.
2026-01-01 | Advances and challenges in the treatment of neurofibromatosis type 1 related plexiform neurofibromatosis in the head and neck
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene located at 17q11.2. Plexiform neurofibromas (PN) are one of the common clinical manifestations of NF1, known as NF1-related plexiform neurofibromas (NF1-PN). Head and neck NF1-PN account for 42.9% of all cases. Tumors grow rapidly during childhood and adolescence, and they can exhibit widespread growth, causing severe head, face, and neck deformities, organ dysfunction, and even loss of function. NF1-PN have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs), known as NF1-associated MPNST (NF1-MPNST). Histopathology is the gold standard for diagnosing NF1-PN, magnetic resonance imaging (MRI) is the preferred imaging examination for NF1-PN, and PET/CT examination is a reliable method for early detection and diagnosis of NF1-MPNST. Genetic testing plays an important role in early diagnosis of tumors, monitoring tumor progression, genetic counseling, and molecular level treatment and management of the disease. This article proposes the goals and principles for treating NF1-PN in the head and neck region. The main treatment methods currently used are surgery and medication. Surgical treatment includes surgical resection, and tissue flap repair or allogeneic transplantation of composite tissue after surgical resection. The mitogen-activated protein kinase inhibitors (MEK) inhibitor Selumetinib is an effective medication used to treat NF1-PN patients aged 3 years and older with symptoms and who are unable to undergo surgery. A Phase Ⅱb trial of mirdametinib, a small-molecule inhibitor, has been completed in adults and children, and it is considered well tolerated in both groups. CRISPR/Cas9 technology is expected to become an effective means of NF1-PN gene therapy. The treatment method of NF1-MPNST is similar to that of soft tissue sarcoma. However, the safety of complete resection of extra-large tumors, protection of important tissues and organs during surgery, effective control of intraoperative bleeding, reconstruction of soft and hard tissue defects in the head and neck; prospective, multicenter, randomized, double-blind, controlled clinical trials of MEK inhibitors, as well as the use of CRISPR/Cas9 technique for gene therapy NF1-PN, are all current challenges. This article summarizes recent advances and ongoing challenges in the treatment of head and neck NF1-PN, aiming to provide a reference for clinicians and researchers.
2025-11-26 | Neurofibromatosis Type 1: Genetic Mechanisms and Advances in Therapeutic Innovation
Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements.
2025-11-20 | Prospects for epigenetic research in neurofibromatosis type 1
Background . Neurofibromatosis type 1 (NF1) is a monogenic disease with a wide range of clinical manifestations. NF1 is associated with increased risk of malignant peripheral nerve sheath tumors (MPNST), leukemia, gastrointestinal and breast cancer, rhabdomyosarcoma, carcinoid tumors, and pheochromocytoma. NF1 gene mutations serve as drivers of various sporadic malignancies. the purpose of the study was to evaluate the mechanisms by which epigenetic factors influence the development of NF1 and the potential for their use in diagnosis and treatment. Material and Methods . The search for relevant sources was carried out in Scopus, Web of Science, PubMed, Elibrary, including publications from February 1995 to February 2025. Of the 1432 scientific articles found, 56 were used to write the review. Results . An analysis of scientific literature showed that NF1 mRNA is a target of 13 microRNAs that are also involved in carcinogenesis of sporadic nervous system tumors (miR-9, miR-10b, miR-16, miR-21, miR-27a, miR-27b-3p, miR-34a, miR125a-3p, miR-128-3p, miR-137-3p, miR-147a, miR-193b, miR-204-5p). There is evidence of an evolutionary and functional relationship between NF1 gene and retroelements: the formation of 12 NF1 pseudogenes on 7 different chromosomes with the help of retroelement enzymes, NF1 introns contain Alu and LINE, which are sources of alternative splicing and recombination, and the presence of insertional mutagenesis hot spots in NF1. Conclusion . Genetic studies have not confirmed the role of modifier genes as triggers for the development and progression of tumor syndrome in NF1. However, changes in the expression of specific microRNAs have been identified in the development of cutaneous, subcutaneous, and plexiform neurofibromas, MPNST. This suggests the potential of studying of epigenetic factors in NF1 pathogenesis for targeted therapy. Further studies of the relationship between the NF1 gene and retroelements will identify new treatment options for NF1 and sporadic tumors by addressing the “vicious cycle” described in the relationship between other tumor suppressor genes and retroelements.
cell therapies
2026-05-18 | Large-Scale Assessment of NF1 Single Amino Acid Variants as HLA Class I Neoantigens.
Neoantigens are cancer-specific antigens arising from genomic alterations. Single Amino Acid Variants (SAAVs) represent a primary class of these neoantigens. To evaluate the therapeutic potential of Neurofibromin 1 (NF1)-derived SAAVs - given that NF1 is frequently mutated in malignant brain tumors - we prioritized the 40 NF1 SAAVs determined to be HLA-A*02:01 binders using computational prediction coupled with experimental validation. To validate these predicted neoepitopes, we employed a two-tiered experimental approach in HLA-A*02:01 homozygous U87-MG cells. We first synthesized minigene constructs encoding the predicted neoepitopes, introduced them via lentiviral transfection and confirmed their expression by mass spectrometry (MS). Subsequently, we performed endogenous validation using pan-HLA immunoprecipitation mass spectrometry (IP-MS), confirming 4 (10 neoepitopes) of the 40 candidate SAAVs. We observed a discrepancy between in silico predictions and the observed sequences. Our endogenous peptidomics further revealed conserved peptide motifs and demonstrated that peptide selection for HLA presentation is transient. While our study substantiates the therapeutic feasibility of T-cell immunotherapies targeting NF1 mutations, these results underscore a limitation in current computational prediction. Our study highlights the necessity of experimental validation to refine neoantigen prioritization strategies.
2026-04-02 | Identification of CD74-positive antigen presenting glioma cells in primary human tumors and murine models of NF1 high-grade glioma.
Compared to the general population, individuals with Neurofibromatosis Type 1 have a 50-fold higher risk of developing a high-grade glioma (HGG) in their lifetime. Despite improved understanding of the molecular and cellular drivers of these neoplasms, we have yet to translate this knowledge into therapies that improve overall survival. One limitation has been the paucity of in vivo models for drug testing within this population. We generated 3 distinct glioma stem cell lines from high-grade gliomas arising in mice with Nf1 and Trp53 mutations in cis (NPcis) and characterized the allografts resulting from one Nf1-glioma stem cell line (Nf1-HGG17) by single cell and single nuclear RNA-seq. Because our cell lines are grown in stem cell media, there is an inherent reduction of the differentiation states present in primary HGG, with only oligodendrocyte precursor-like and neural-like cells identified. However, orthotopic allografts of Nf1-HGG17 regained the other differentiation states typically observed in HGG and GBM (neuronal progenitor cell-like and astrocyte-like). About half of neoplastic cells cluster separately from these classical groups and highly express genes of the antigen presentation machinery, including Cd74, which we also observed in patient samples. Notably, heterozygosity of Nf1 within the tumor microenvironment does not cause marked changes in the immune tumor microenvironment, gene expression, or differentiation states of neoplastic cells. These data indicate that allografted HGG lines from NPcis mice are an effective model of NF1-HGG, mimicking the complexity observed in human HGG, that can be used for larger scale in vivo drug screening and evaluation.
2026-01-17 | Asthma-mediated control of optic glioma growth via T cell-microglia interactions: A mathematical model.
Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. A connection between asthma and optic glioma has previously been observed, but the mechanisms are unclear. To elucidate the role of asthma in the regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in the regulation of microglia, a key player in the glioma tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that inflammation can play a key role in suppressing the proliferation of optic glioma cells via immune reprogramming of T cells and the delicate control of signaling networks in microglia. Our mathematical model unveils the complex interactions between tumor and immune cells in optic glioma. Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.
2025-09-22 | Circumferentially Exposed Achilles Tendon Wound Reconstruction Using Free Anterolateral Thigh Flap With Vascularized Fascia Lata Wrapping.
Resection of a giant plexiform fibroma on the lower leg of a 75-year-old woman with neurofibromatosis type 1 resulted in an extensive skin soft tissue defect and a circumferentially exposed wound involving the Achilles tendon. As secondary reconstruction was performed after a waiting period to rule out a malignant peripheral nerve sheath tumor using histopathological examination, the major challenge was to prevent adhesion of the Achilles tendon to the surrounding granulation tissue, in addition to reconstructing the extensive skin soft tissue defect. We overcame this problem by using a free anterolateral thigh flap with the vascularized fascia lata wrapping technique. A free composite anterolateral thigh flap with fascia lata is a recognized method for primary reconstruction of the Achilles tendon and overlying soft tissue defects. We selected this method not for reconstruction of the Achilles tendon defect, but to prevent adhesion of the tendon to the surrounding tissue. The exposed Achilles tendon was circumferentially wrapped with vascular fascia lata. The postoperative range of motion of the ankle joint was 5 degrees in dorsiflexion and 45 degrees in plantar flexion. Although dorsiflexion was impaired, the patient was able to walk unassisted and had no problems in daily life. The appearance around the ankle joint was good. We report the novel use of a free anterolateral thigh flap with vascularized fascia lata in periapical Achilles tendon reconstruction.
2025-09-02 | Evaluating CAR-T cells from neurofibromatosis type 1 (NF1) patients for targeting AXL in malignant peripheral nerve sheath tumors associated with NF1.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by neurofibromas, with 5-13% of patients risk developing malignant peripheral nerve sheath tumors (MPNST). Current treatments for MPNST are largely ineffective. AXL, overexpressed in MPNST, is a potential target for Chimeric Antigen Receptor T (CAR-T) cell therapy. This study evaluates the immunophenotypes, efficacy, and safety of NF1-derived AXL-CAR-T cells in treating MPNST. AXL-CAR-T cells, containing an anti-AXL single-chain variable fragment, were derived from NF1 patients (n = 27) and healthy donors (n = 15). Immunophenotypes were characterized using CCR7, CD45RA, CD4, and CD8 markers. The cytotoxicity of CAR-T cells was tested in vitro against MPNST cells, and efficacy and safety were evaluated in an MPNST xenograft mouse model. Multiplex immunoassays and ELISA measured cytokines and granzyme b release. AXL-CAR-T cells from both NF1 patients and healthy donors had a similar partition in stem cell-like memory T cell composition and comparable ex vivo expansion. AXL-CAR-T cells from both groups effectively lysed MPNST cells in vitro. In vivo, tumor volumes in xenograft mice were significantly reduced with no on-target off-tumor toxicity. NF1 patient-derived AXL-CAR-T cells demonstrated similar quality and efficacy to those from healthy donors, supporting their potential autologous therapy for MPNST.
small molecules
2026-08-11 | Combined FAK and MEK inhibition suppresses chromosome 8 gain malignant peripheral nerve sheath tumors.
Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.
2026-08-05 | DNA Hypomethylation Is Not Cell Intrinsically Toxic to Polycomb Repressive Complex 2 Deficient Malignant Peripheral Nerve Sheath Tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for neurofibromatosis type 1 (NF1) patients. In the context of NF1, MPNSTs develop from benign premalignant precursors and the transition to malignancy is typically accompanied by loss of the polycomb repressive complex 2 (PRC2), which results in aberrant upregulation of over 1200 genes due to global depletion of histone H3 lysine 27 trimethylation (H3K27me3). Previous studies suggest cells compensate for the loss of this repressive histone mark via hypermethylation of the genome. Here we analyzed genome-wide DNA methylation and the transcriptome in MPNST cell lines and isogenic PRC2-deficient and -proficient CRISPR-engineered immortalized human Schwann cells. In addition to effects of PRC2 status, we also measured the effects of two DNA methyltransferase inhibitors (DNMTi), decitabine and azacitidine. We found that PRC2 status does not affect global DNA methylation or average methylation levels across specific genomic features. Furthermore, decitabine and azacitidine have differential effects on MPNSTs. While both DNMTis hypomethylate the genome, they upregulate different targets. Azacitidine upregulates genes involved in RNA processing pathways and exhibits direct tumor cell cytotoxicity, while decitabine upregulates genes involved in the immune response, has no direct-cell killing effects, and likely suppresses tumor growth in vivo by altering the tumor microenvironment. We show that DNA hypomethylation alone is insufficient to kill MPNST cells, regardless of PRC2 status. Consequently, these findings suggest that DNMT inhibitors should be utilized in combination with other targeted therapies for MPNST patients.
2026-08-02 | Case Report: Schwann cell reprogramming and PDGF-driven nerve hypertrophy in an NF1 patient with CIDP-like autoimmunity.
Differentiating neoplastic proliferation from inflammatory fibrosis in peripheral nerve hypertrophy is critical. We report a patient with a neurofibromatosis type 1 (NF1) deletion exhibiting extreme diffuse nerve enlargement and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like autoimmunity. This study aims to elucidate the underlying endoneurial fibrotic mechanism, specifically focusing on the signaling networks between Schwann cells (SCs) and fibroblasts. Single-cell RNA sequencing was performed on a biopsied sural nerve to profile the cellular and transcriptomic landscape. Intercellular interactome and pseudotime trajectory analyses were utilized to map molecular evolution and signaling crosstalk. Transcriptomic profiling revealed that SCs-which normally maintain myelin around axons and support peripheral nerve function-were pathologically entrapped in a dedifferentiated state. Serving as a genetic primer, the NF1 deletion lowered the threshold for SC reprogramming, a vulnerability that was subsequently unleashed by a severe autoimmune infiltrate consisting of macrophages and T cells. These reprogrammed SCs abandoned myelin-maintaining genes, such as MPZ, to acquire a pro-fibrotic phenotype. Through a coordinated platelet-derived growth factor (PDGF) dual-axis network involving PDGFC-PDGFRA and PDGFD-PDGFRB, the entrapped SCs exclusively secreted PDGF ligands that potently activated endoneurial fibroblasts and vascular mural cells. This persistent paracrine signaling orchestrated excessive extracellular matrix deposition, driving a massive expansion of the endoneurial interstitium and the formation of classic "onion bulbs". Our data suggest that the macroscopic hypertrophic changes observed in this specific clinical presentation may reflect an aberrant, immune-triggered fibrotic cascade-where autoimmune leukocyte infiltration continuously drives stromal overgrowth-complementing rather than entirely precluding the classical RAS/MAPK-driven neoplastic SC hyperproliferation. Furthermore, within the limitations of this pilot evaluation, characterizing this potential SC-fibroblast crosstalk indicates that the PDGF signaling pathway may warrant further investigation as a candidate translational therapeutic target for refractory hypertrophic neuropathies.
2026-07-27 | A standardized imaging and analysis workflow for quantitative evaluation of cutaneous neurofibromas in Nf1-KO mice.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder in which cutaneous neurofibromas (cNFs) represent one of the most common and burdensome manifestations. No approved pharmacological treatment exists. Preclinical studies are essential to evaluate candidate therapies, but reliable outcome and endpoint measures for cNFs in animal models remain limited. We developed and validated a standardized methodology to assess drug efficacy in the Prss56Cre Nf1-KO mouse model which recapitulates key features of cNFs. In this model, Nf1 inactivation and tdTomato (Tom) reporter expression were specifically targeted to Schwann cells (SCs) responsible for cNF development. This approach enables real-time monitoring, isolation, and manipulation of tumor SCs at any time. We defined macroscopic (tumor count, total Tom+ fluorescent surface area, fluorescence intensity) and microscopic (cell-type composition defined by immunolabeling with a panel of specific markers, area quantification) endpoints, developed dedicated ImageJ scripts for automated image analysis, and compared the results with those obtained using the conventional manual method. Both automated measurements showed excellent reproducibility (ICC = 1) and strong correlation with manual analysis (Spearman's coefficient > 0.90), while significantly reducing analysis time (up to 100-fold faster). Bland-Altman analyses confirmed the absence of systematic bias compared with manual scoring. The standardized image naming and metadata integration further facilitated data consolidation and statistical analysis. This validated approach provides a reliable, reproducible, and time-efficient framework for evaluating drug effects on cNFs in preclinical studies. It establishes a foundation for robust efficacy testing of candidate therapies, facilitates cross-study comparability, and accelerates therapeutic development and clinical translation.
2026-07-22 | Carboplatin induces optic nerve oligodendrocyte loss and impairs myelin sheath microstructure in a mouse model of neurofibromatosis type 1 (NF1).
Vision impairment is a significant concern for children with Neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). While carboplatin-containing chemotherapy is often first-line therapy for NF1-OPG, it does not consistently improve visual function. Furthermore, chemotherapy is associated with altered white matter microstructure in individuals with NF1-OPG, suggesting a detrimental effect on oligodendroglia. We analyzed the tumor-independent effects of carboplatin on oligodendrocytes in Nf1-mutant mice and evaluated pharmacological strategies for reducing this chemotherapy-associated toxicity. Carboplatin- or vehicle-treated Nf1+/- mice or Nf1-mutant optic glioma cells were employed to assess the effects of restorative interventions on optic nerve oligodendrocytes in vivo and tumor cell growth in vitro, respectively. Clinically relevant carboplatin dosing induced oligodendrocyte loss and impaired myelin sheath structure in the optic nerves of Nf1+/- mice, an effect not observed following vinca alkaloids or MEK inhibitor (selumetinib) treatment. Carboplatin downregulates genes essential for cholesterol biosynthesis and decreases cholesterol levels in carboplatin-exposed Nf1+/- optic nerves, such that dietary cholesterol supplementation after carboplatin exposure restored oligodendrocyte numbers. Carboplatin also increases the density of monocytes (microglia/macrophages) in the Nf1+/- optic nerves. Using PLX5622 (a CSF1R inhibitor) to reduce monocytes numbers or using clemastine to promote the generation and survival of oligodendrocytes, alleviated the oligodendrocyte loss caused by carboplatin treatment. Notably, PLX5622 and clemastine reduced the viability of Nf1-mutant optic glioma tumor cells. Our findings demonstrate that carboplatin induces oligodendroglial toxicity in Nf1-mutant optic nerves, which can be mitigated by clemastine, PLX5622, or dietary cholesterol following carboplatin exposure.
proteins
2025-07-01 | Single-cell tumor microenvironment profiling informs a circulating proteome test for the interception of malignant transformation in NF1 nerve sheath tumors.
The most common cause of death in neurofibromatosis type 1 (NF1) is the development of malignant peripheral nerve sheath tumor (MPNST), a deadly sarcoma that can transform from benign plexiform neurofibromas (PN) or premalignant atypical neurofibromas (AN). We built a single-cell dataset of 55 NF1-associated PN, AN, and MPNST to define cellular changes in neurofibroma at-risk of malignant transformation. Integrative analysis of changes in the tumor microenvironment revealed the emergence of malignant tumor cells, regulatory T cells, and loss of activated macrophages in MPNST. Using this reference dataset, we validated findings using anchor-based label transfer in an additional 19 NF1 nerve sheath tumors profiled with single cell sequencing, and public datasets. We then defined protein biomarkers of malignant transformation from high-throughput proteomic analysis of plasma samples collected from 45 NF1 patients that correlated to mRNAs specific to MPNST cell populations. Fifty plasma proteins accurately and non-invasively distinguished patients with MPNST from those with premalignant tumors. These markers should improve the ability to identify high-risk neurofibromas for improved cancer surveillance and enable early detection of malignant transformation in NF1.
2024-09-14 | Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.
Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.
2024-08-22 | Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues.
The neurofibromatosis type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we performed spatial transcriptomics to define the molecular signatures occurring during normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-β, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1fl/- (Nf1Postn) fracture callus. Transcriptional analyses, subsequently confirmed through phospho-SMAD1/5/8 immunohistochemistry, demonstrated a lack of BMP pathway induction in Nf1Postn mice. To gain further insight into the human condition, we performed spatial transcriptomic analysis of fracture pseudarthrosis tissue from a patient with NF1. Analyses detected increased MAPK signaling at the fibrocartilaginous-osseus junction. Similar to that in the Nf1Postn fracture, BMP pathway activation was absent within the pseudarthrosis tissue. Our results demonstrate the feasibility of delineating the molecular and tissue-specific heterogeneity inherent in complex regenerative processes, such as fracture healing, and reconstructing phase transitions representing endochondral bone formation in vivo. Furthermore, our results provide in situ molecular evidence of impaired BMP signaling underlying NF1 pseudarthrosis, potentially informing the clinical relevance of off-label BMP2 as a therapeutic intervention.
2024-07-12 | The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.
2024-03-27 | Estrogen-induced glial IL-1β mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma.
Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1β (IL-1β), which is neurotoxic to RGCs in vitro. Importantly, both IL-1β neutralization and leuprolide-mediated estrogen suppression decrease IL-1β expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss.
antibodies
2026-05-04 | Immune landscape characterization of neurofibromas with atypical features in Neurofibromatosis1 reveals PD-1 and the Tim-3/Galectin-9 pathway as potential therapeutic targets.
Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to the development of plexiform neurofibromas (pNF), benign tumors of the nerve sheath that can progress to malignant peripheral nerve sheath tumors (MPNST). Some pNFs exhibit atypical characteristics, particularly atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), which meet recently defined criteria. These are pNFs with concerning histological and/or molecular features and uncertain behavior, leading to their consideration as potential precursors of MPNSTs. In this study, we characterized the immune landscape of a series of atypical neurofibromas (exhibiting increased cellularity or atypical cells) and ANNUBPs (ANF/ANNUBP) compared to cutaneous neurofibromas (cNF), pNFs, and MPNSTs, all from patients with NF1, using immunohistochemistry and single-cell RNA sequencing (scRNA-seq). Our findings revealed that ANF/ANNUBPs are heavily infiltrated with CD3+ T-lymphocytes and CD163+ macrophages. Transcriptomic profiling using the NanoString technology demonstrated that ANF/ANNUBPs exhibit a distinct immune signature compared to both pNFs and MPNSTs. This includes overexpression of two inhibitory immune checkpoints (ICs): HAVCR2 (encoding the IC receptor Tim-3) and its primary ligand Galectin-9 (Gal9). Subsequent analyses of scRNA datasets corroborated these findings with Prss56Cre/+, Nf1fl/fl, R26tdTom/+ mouse model-derived tumors. Using multiplex immunofluorescence, we showed that CD3+ T-cells express the inhibitory IC PD-1, while CD163+ macrophages express both Tim-3 and Gal9. Furthermore, tumor cells within ANF/ANNUBPs were positive for activated caspase-3, suggesting a possible role of the immune microenvironment in controlling tumor growth or inducing cell death. Through deep-targeted DNA sequencing, we detected loss of cell cycle regulators (especially CDKN2A) in ANF/ANNUBPs but no somatic alteration of polycomb repressor complex components EED and SUZ12, the latter typically associated with MPNSTs, even at low frequencies. Additionally, loss of H3K27me3 was associated with even lower densities of CD3+ T-cells and CD163+ macrophages in MPNSTs, and the loss of p16 seemed to act synergistically. Taken together, these findings suggest that an immune response involving both T-lymphocytes and macrophages may play a role in controlling or delaying the malignant transformation of ANF/ANNUBPs into MPNSTs and point to IC molecules as novel immunopreventive strategies in NF1 patients with ANF/ANNUBPs.
2026-04-10 | The Cell Surface Proteome of Malignant Peripheral Nerve Sheath Tumors Reveals Therapeutic Targets.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for Neurofibromatosis Type 1 (NF1) patients. In the context of NF1, MPSNTs develop from benign premalignant precursors. The transition to malignancy is usually accompanied by loss of the polycomb repressive complex 2 (PRC2), leading to aberrant upregulation of many genes. The specific mechanisms disrupted by PRC2 loss remain incompletely understood. There is a significant gap in our knowledge of which cell-surface targets become derepressed and therapeutically actionable following PRC2 loss, contributing to the current lack of effective targeted therapies for MPNSTs. This study aims to address this gap by using cell-surface capture technology with mass spectrometry to profile MPNST models. In doing so, we define PRC2-dependent effects on the cell surface proteome, including specific biological pathways that are enhanced or suppressed at the cell surface protein level. We also create an MPNST cell-surface protein compendium comprised of proteins that are highly expressed across a variety of well-defined MPNST models. We prioritized proteins that are preferentially expressed in MPNST or other cancers and for which FDA-approved therapies already exist. Specific proteins from this compendium were molecularly targeted with antibody-drug conjugates in these models to surmise their therapeutic efficacy. Results reveal PTK7 as a novel and promising target for MPNST. In total, these efforts represent a step toward addressing the knowledge gap in MPNST genesis and identifying new therapeutic targets for further testing. Additionally, this data serves as a resource for other researchers wishing to characterize specific molecular targets.
2026-03-02 | IFN signaling at the nexus of the radiotherapy response in malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that constitute a major cause of mortality in individuals with neurofibromatosis type 1 (NF-1) and exhibit highly variable responses to radiotherapy. In this issue of the JCI, Zhu and colleagues integrated functional genomics, single-cell transcriptomics, and analysis of human tumors to show that type I IFN signaling shapes both tumor-intrinsic radiation sensitivity of MPNSTs and local recruitment and activation of T cells. Their findings establish IFN signaling as a central coordinator of the radiotherapy response in MPNSTs and suggest that incorporating targeted immunomodulation strategies may improve radiotherapy outcomes. The work also has direct implications for the role of the immune system and IFN signaling radiation-based treatment of soft tissue sarcomas beyond those involved in NF-1.
2026-01-27 | FAP expression as a marker of malignant transformation enabling in vivo characterization in peripheral nerve sheath tumors: a multimodal and translational study.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and a major cause of mortality in neurofibromatosis type 1 (NF-1). Distinguishing MPNSTs from benign neurofibromas remains challenging. We investigated fibroblast activation protein alpha (FAP) as a malignancy biomarker and theranostic target in peripheral nerve sheath tumors. Therefore, we integrated publicly available bulk transcriptomics, spatial transcriptomics, and single-cell RNA sequencing with immunohistochemistry (IHC) on independent archival samples. We further directly assessed clinical translatability using FAP-targeted PET/CT in an NF-1 patient undergoing work-up for suspected malignant transformation. Across independent bulk datasets, FAP was consistently up-regulated in MPNSTs compared with neurofibromas. In the TCGA sarcoma dataset, FAP varied by histotype but was clearly expressed in MPNSTs. Spatial transcriptomics revealed enrichment of FAP-high regions in MPNSTs and co-localization with tumor cell markers. Single-cell analysis showed FAP expression in MPNST tumor cells and cancer-associated fibroblasts, with the highest levels in neural crest-like tumor subpopulations previously linked to adverse prognosis; pseudotime analysis indicated decreasing FAP expression along trajectories toward Schwann cell precursor-like states linking FAP expression to a more primitive, dedifferentiated tumor cell state. IHC confirmed strong, predominantly tumor cell-intrinsic FAP expression in MPNSTs, with minimal staining in neurofibromas and normal tissues. Plexiform neurofibromas exhibited intermediate FAP expression. In clinical imaging, FAP-PET demonstrated higher tracer uptake in histologically proven MPNSTs than in benign lesions within the same patient, including a neurofibroma that was FDG-avid but FAP-negative, supporting added diagnostic specificity over FDG-PET/CT. In summary, FAP is robustly overexpressed in MPNSTs at transcript and protein levels, potentially concentrates in high-risk tumor cell states, and is detectable by targeted PET imaging. These findings identify FAP as a clinically relevant biomarker for malignancy in NF-1-associated tumors and support implementation of FAP-directed diagnostics and therapeutics in peripheral nerve sheath tumor work-up.
2025-11-17 | A novel germline NF1 splicing variant drives the onset of an anorectal mucosal melanoma in a patient with a stable and durable nivolumab response.
Neurofibromatosis type-1 (NF1) patients rarely develop mucosal melanomas. We report a rare form of anorectal mucosal melanoma (ARMM) in an NF1 syndromic patient profiled for genomics and transcriptomics to assess the determinants of the response to nivolumab. Primary melanoma and metastases were analyzed with targeted sequencing and gene expression profile (tGEP). We applied in silico (cBioPortal and predictor tools) and in vitro (hybrid minigene) approaches to confirm the variant pathogenicity. We detected the novel c.4269+2_4269+3delTG germline splicing variant in NF1, which proved to be pathogenic by the minigene assay showing an aberrant splicing. The tumor showed a copy-number (CN) neutral loss of heterozygosity for the WT allele, and both ARMM and metastases carried several CN gains associated with NF1-driven carcinogenesis and very low mutation burden. The tGEP analysis unveiled a macrophagic infiltration, with a pro-inflammatory M1-type polarization, in the context of lack of PD-L1 expression. The response to nivolumab in a germline NF1-driven ARMM case seems independent from levels of TMB and PD-L1 expression and may be mediated by inflammatory response induced by M1-polarized macrophages.
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2026-02-13 | Proof-of-principle of NF1 gene therapy in plexiform neurofibroma xenograft mouse models.
Neurofibromatosis type I is a rare neurocutaneous syndrome characterized by the development of disfiguring neurofibroma tumors with unmet clinical needs. As Neurofibromatosis Type I is a monogenic disease, the development of gene therapy is highly attractive, but it is currently unknown if rescuing the NF1 gene in established neurofibroma is sufficient for tumor regression. Here, we test this hypothesis by building two novel NF1 mouse models with reversible NF1 expression. In the first model, the human NF1 -/- Schwann cells named ipNF95.11b C/T are genetically modified with a doxycycline-inducible full-length mouse Nf1 gene. One month after cells implantation in the sciatic nerve, mice are split into two treatment groups and received either doxycycline or control water. Strikingly, most sciatic nerves from mice allowed to drink doxycycline water for one month do not display neurofibroma histologically (2 out of 16 sciatic nerves, 13%) whereas 75% (12 out of 16 sciatic nerves) develop or maintain a neurofibroma when drinking control water. In the second model, the human NF1 +/- Schwann cells named ipNF95.11 C are genetically modified with a doxycycline-inducible potent shRNA against the NF1 mRNA transcript. Strikingly, doxycycline withdrawal after neurofibroma establishment allowed limited neurofibroma maintenance (3 out of 14 sciatic nerves, 21%), whereas most sciatic nerves showed evidence of neurofibroma when kept on doxycycline (12 out of 14 sciatic nerves, 86%). Finally, intrathecal injection of the full-length Nf1 lentivirus in established 1-month ipNF95.11b C/T xenograft pNF significantly reduced tumor burden. All mice are female. Thus, we provide proof-of-principle of the efficacy of NF1 Gene Therapy in plexiform neurofibroma mice models, paving the way to the development of therapeutic gene therapy solutions for NF1 patients.
2026-02-13 | Neurofibromin 1 (NF1) Splicing Mutation c.61-2A>G: From Aberrant mRNA Processing to Therapeutic Implications In Silico.
The neurofibromin 1 (NF1) splice-site mutation c.61-2A>G (rs1131691100) is a rare, pathogenic, autosomal dominant variant that disrupts NF1 tumor-suppressor function, causing neurofibromatosis type 1 (NF1). Its pathogenic mechanism is poorly understood, and the potential for personalized therapeutic genome editing remains unknown due to the absence of a standard framework for investigating splicing disorders. Here, we performed a comprehensive multi-omics analysis of a de novo c.61-2A>G case from South Korea, integrating short- and long-read whole genome sequencing, whole transcriptome sequencing, and methylation profiling. We confirm that c.61-2A>G abolishes the canonical splice acceptor site, activating a cryptic splice acceptor 16 nucleotides downstream in exon 2. This splicing shift generates a 16-nucleotide deletion, causing a frameshift and premature stop codon that truncates the protein's N-terminal region. Long-read sequencing further reveals that the mutation creates a novel CpG dinucleotide, which is methylated in the majority of reads. Finally, we assessed therapeutic correction strategies, revealing that CRISPR-Cas9 prime editing is the only viable approach for in vivo correction. This study provides the first comprehensive multi-omics characterization of the NF1 c.61-2A>G mutation and establishes a minimal framework for precision therapeutic development in silico in monogenic splicing disorders.
2026-01-01 | Advances and challenges in the treatment of neurofibromatosis type 1 related plexiform neurofibromatosis in the head and neck
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene located at 17q11.2. Plexiform neurofibromas (PN) are one of the common clinical manifestations of NF1, known as NF1-related plexiform neurofibromas (NF1-PN). Head and neck NF1-PN account for 42.9% of all cases. Tumors grow rapidly during childhood and adolescence, and they can exhibit widespread growth, causing severe head, face, and neck deformities, organ dysfunction, and even loss of function. NF1-PN have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs), known as NF1-associated MPNST (NF1-MPNST). Histopathology is the gold standard for diagnosing NF1-PN, magnetic resonance imaging (MRI) is the preferred imaging examination for NF1-PN, and PET/CT examination is a reliable method for early detection and diagnosis of NF1-MPNST. Genetic testing plays an important role in early diagnosis of tumors, monitoring tumor progression, genetic counseling, and molecular level treatment and management of the disease. This article proposes the goals and principles for treating NF1-PN in the head and neck region. The main treatment methods currently used are surgery and medication. Surgical treatment includes surgical resection, and tissue flap repair or allogeneic transplantation of composite tissue after surgical resection. The mitogen-activated protein kinase inhibitors (MEK) inhibitor Selumetinib is an effective medication used to treat NF1-PN patients aged 3 years and older with symptoms and who are unable to undergo surgery. A Phase Ⅱb trial of mirdametinib, a small-molecule inhibitor, has been completed in adults and children, and it is considered well tolerated in both groups. CRISPR/Cas9 technology is expected to become an effective means of NF1-PN gene therapy. The treatment method of NF1-MPNST is similar to that of soft tissue sarcoma. However, the safety of complete resection of extra-large tumors, protection of important tissues and organs during surgery, effective control of intraoperative bleeding, reconstruction of soft and hard tissue defects in the head and neck; prospective, multicenter, randomized, double-blind, controlled clinical trials of MEK inhibitors, as well as the use of CRISPR/Cas9 technique for gene therapy NF1-PN, are all current challenges. This article summarizes recent advances and ongoing challenges in the treatment of head and neck NF1-PN, aiming to provide a reference for clinicians and researchers.
2025-11-26 | Neurofibromatosis Type 1: Genetic Mechanisms and Advances in Therapeutic Innovation
Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements.
2025-11-20 | Prospects for epigenetic research in neurofibromatosis type 1
Background . Neurofibromatosis type 1 (NF1) is a monogenic disease with a wide range of clinical manifestations. NF1 is associated with increased risk of malignant peripheral nerve sheath tumors (MPNST), leukemia, gastrointestinal and breast cancer, rhabdomyosarcoma, carcinoid tumors, and pheochromocytoma. NF1 gene mutations serve as drivers of various sporadic malignancies. the purpose of the study was to evaluate the mechanisms by which epigenetic factors influence the development of NF1 and the potential for their use in diagnosis and treatment. Material and Methods . The search for relevant sources was carried out in Scopus, Web of Science, PubMed, Elibrary, including publications from February 1995 to February 2025. Of the 1432 scientific articles found, 56 were used to write the review. Results . An analysis of scientific literature showed that NF1 mRNA is a target of 13 microRNAs that are also involved in carcinogenesis of sporadic nervous system tumors (miR-9, miR-10b, miR-16, miR-21, miR-27a, miR-27b-3p, miR-34a, miR125a-3p, miR-128-3p, miR-137-3p, miR-147a, miR-193b, miR-204-5p). There is evidence of an evolutionary and functional relationship between NF1 gene and retroelements: the formation of 12 NF1 pseudogenes on 7 different chromosomes with the help of retroelement enzymes, NF1 introns contain Alu and LINE, which are sources of alternative splicing and recombination, and the presence of insertional mutagenesis hot spots in NF1. Conclusion . Genetic studies have not confirmed the role of modifier genes as triggers for the development and progression of tumor syndrome in NF1. However, changes in the expression of specific microRNAs have been identified in the development of cutaneous, subcutaneous, and plexiform neurofibromas, MPNST. This suggests the potential of studying of epigenetic factors in NF1 pathogenesis for targeted therapy. Further studies of the relationship between the NF1 gene and retroelements will identify new treatment options for NF1 and sporadic tumors by addressing the “vicious cycle” described in the relationship between other tumor suppressor genes and retroelements.
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Drug Discovery Landscape
10 orphan drug designations for Neurofibromatosis type 1, including 6 approved therapies.
10 orphan drug designations for Neurofibromatosis type 1, including 6 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Nitroxoline | small molecules | FDA | 2023-07-17 | — | Healx Limited |
2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide | small molecules | EMA | 2023-05-22 | — | FGK Representative Service GmbH |
2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide | small molecules | FDA | 2021-08-12 | — | Nflection Therapeutics, Inc. |
allosteric MEK 1/2 inhibitor | small molecules | FDA | 2020-11-03 | — | Pasithea Therapeutics Corp. |
N-((R)-2,3-dihydroxypropoxyl)-3,4-difluro-2-(2-fluoro-4-iodo-phenylamino)-benzamide [Ezmekly] | small molecules | EMA | 2019-07-25 | 2025-07-18 | Merck Europe B.V. |
mirdametinib [Gomekli] | small molecules | FDA | 2018-10-30 | 2025-02-11 | SpringWorks Therapeutics, Inc. |
Selumetinib [Koselugo] | small molecules | EMA | 2018-07-31 | 2021-06-19 | AstraZeneca AB |
selumetinib [Koselugo] | small molecules | FDA | 2018-02-14 | 2025-09-10 | AstraZeneca Pharmaceuticals LP |
selumetinib [Koselugo] | small molecules | FDA | 2018-02-14 | 2025-09-10 | AstraZeneca Pharmaceuticals LP |
selumetinib [Koselugo] | small molecules | FDA | 2018-02-14 | 2025-09-10 | AstraZeneca Pharmaceuticals LP |
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