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:
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.
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.
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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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