RARE DISEASE
Full NF2-related schwannomatosis
Full NF2-related schwannomatosis
Full NF2-related schwannomatosis
Synonyms: Full NF2, Full neurofibromatosis type 2, Nonmosaic NF2-related schwannomatosis, Nonmosaic neurofibromatosis type 2
Synonyms: Full NF2, Full neurofibromatosis type 2, Nonmosaic NF2-related schwannomatosis, Nonmosaic neurofibromatosis type 2
Synonyms: Full NF2, Full neurofibromatosis type 2, Nonmosaic NF2-related schwannomatosis, Nonmosaic neurofibromatosis type 2
Drug discovery
6
drugs
With orphan designations
Overview
NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant disorder caused by pathogenic NF2 gene variants, leading to Merlin tumor suppressor protein dysfunction. It manifests with bilateral vestibular schwannomas, meningiomas, and ependymomas, causing hearing loss, neurological deficits, and visual impairment. Diagnosis relies on clinical criteria (e.g., bilateral vestibular schwannomas), neuroimaging, and genetic testing. Tumorigenesis involves disrupted Hippo/YAP signaling and aberrant cell proliferation. Management includes surveillance and multimodal therapies targeting tumor growth [1][6][12].
Therapies
Surgical resection or stereotactic radiosurgery for symptomatic tumors [3][16][20].
Molecular therapies (e.g., brigatinib, ALK/FAK inhibitors) showing tumor stabilization in clinical trials [3][13][19].
Investigational approaches: antisense oligonucleotides, gene therapy, and combination therapies [8][10][13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare transplant-related disorders
Research Papers
534 drug discovery papers about Full NF2-related schwannomatosis, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
534 drug discovery papers about Full NF2-related schwannomatosis, with 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-04-10 | Single-cell and spatial transcriptomics analyses reveal tumor microenvironment-driven proliferation of NF2-associated vestibular schwannomas.
The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME among NF2-related schwannomatosis (NF2-SWN) patients with different clinical phenotypes, explore the reasons for these differences, and identify targets for treatment while gaining a deeper understanding of the pathogenesis of the disease. 20 vestibular schwannomas (VSs) from 20 clinically diagnosed NF2-SWN patients, including 11 milder patients (Gardner) and 9 severe patients (Wishart), were analyzed. Single-cell sequencing, TCR sequencing, spatial transcriptomics analysis, multiplex immunofluorescence, immunohistochemistry, and cell experiments were performed to compare the TME of Gardner and Wishart and to elucidate the mechanisms underlying these differences. Our results revealed that NF2-VS consist of 12 significant cell subpopulations, with Gardner and Wishart presenting distinct TME. Wishart exhibited more pronounced immune suppression. Conversely, CD8+ T cells from Gardner demonstrated potential for clonal proliferation. In macrophages, a subtype exhibited higher capacity of angiogenesis and high inflammatory cytokine activity was identified in Wishart, suggested its role in promoting tumor progression. Moreover, we found fibroblasts in Wishart showed excessive stromal deposition, potentially indicated the existence of immunologic barrier. Receptor‒ligand pair analysis revealed that Schwann cells in Wishart regulate immune cell activity via pleiotrophin (PTN), PTN positivity promotes anti-inflammatory cytokine activity, contributing to the formation of an immunosuppressive microenvironment to promote tumor progression. In summary, our study provides an in-depth analysis of the TME of NF2-VS, revealing the differences between Wishart and Gardner. Our study explains how Schwann cells influence the immune landscape to promote tumor development and clarifies the role of the TME in NF2-SWN progression, establishing a theoretical and experimental foundation for future immunotherapeutic strategies for NF2-SWN.
2023-02-28 | Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.
Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay to show that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus close to each other. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Gel filtration experiments showed that dimerization occurs after a PIP2 mediated transition from closed to open conformation monomers. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
2015-06-05 | Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.
2012-04-19 | Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.
Neurofibromatosis type 2 (NF2) is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene. Patients with NF2 develop hallmark schwannomas that require surgery or radiation, both of which have significant adverse effects. Recent studies have indicated that the tumor microenvironment-in particular, tumor blood vessels-of schwannomas may be an important therapeutic target. Furthermore, although much has been done to understand how merlin, the NF2 gene product, functions as a tumor suppressor gene in schwannoma cells, the functional role of merlin in the tumor microenvironment and the mechanism(s) by which merlin regulates angiogenesis to support schwannoma growth is largely unexplored. Here we report that the expression of semaphorin 3F (SEMA3F) was specifically downregulated in schwannoma cells lacking merlin/NF2. When we reintroduced SEMA3F in schwannoma cells, we observed normalized tumor blood vessels, reduced tumor burden, and extended survival in nude mice bearing merlin-deficient brain tumors. Next, using chemical inhibitors and gene knockdown with RNA interference, we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1. This study shows that, in addition to the tumor-suppressing activity of merlin, it also functions to maintain physiological angiogenesis in the nervous system by regulating antiangiogenic factors such as SEMA3F. Restoring the relative balance of proangiogenic and antiangiogenic factors, such as increases in SEMA3F, in schwannoma microenvironment may represent a novel strategy to alleviate the clinical symptoms of NF2-related schwannomas.
2008-06-12 | Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells.
Schwannomas that occur spontaneously or in patients with neurofibromatosis Type 2, lack both alleles for the tumor suppressor and plasma membrane-cytoskeleton linker merlin. We have shown that human primary schwannoma cells display activation of the RhoGTPases Rac1 and Cdc42 which results in highly dynamic and ongoing protrusive activity like ruffling. Ruffling is an initial and temporally limited step in the formation of intercellular contacts like adherens junctions that are based on the cadherin-catenin system. We tested if there is a connection between Rac1-induced ongoing ruffling and the maintenance, stabilization and functionality of adherens junctions and if this is of relevance in human, merlin-deficient schwannoma cells. We show intense ongoing ruffling is not limited to membranes of single human primary schwannoma cells, but occurs also in membranes of contacting cells, even when confluent. Live cell imaging shows that newly formed contacts are released after a short time, suggesting disturbed formation or stabilization of adherens junctions. Morphology, high phospho-tyrosine levels and cortactin staining indicate that adherens junctions are immature in human primary schwannoma cells, whereas they display characteristics of mature adherens junctions in human primary Schwann cells. When merlin is reintroduced, human primary schwannoma cells show only initial ruffling in contacting cells and adherens junctions appear more mature. We therefore propose that ongoing Rac-induced ruffling causes immature adherens junctions and leads to impaired, nonfunctional intercellular adhesion in aggregation assays in merlin-deficient schwannoma cells that could be an explanation for increased proliferation rates due to loss of contact inhibition or tumor development in general.
antibodies
2026-05-17 | A review of targeted therapies for NF2-related vestibular schwannoma: molecular pathogenesis, emerging therapeutics, and future clinical horizons.
Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome driven by mutations in the NF2 gene. The mutation leads to aberrant proliferation of Schwann cells along the vestibular division of cranial nerve VIII, resulting in bilateral vestibular schwannomas (VS) that cause progressive hearing loss and neurological dysfunction. Loss of the tumor suppressor merlin results in dysregulation of multiple oncogenic pathways, including VEGF, MAPK/ERK, PI3K/AKT/mTOR, EGFR/ErbB, PDGFR, and Hippo-YAP. The inability of conventional management modalities to address the multifocal and progressive nature of NF2-associated tumors has driven investigation into targeted therapies. This review summarizes the evolving landscape of targeted therapies in NF2-associated vestibular schwannomas. Management of NF2-VS is individualized, with active surveillance favored for stable or smaller tumors, surgical resection pursued for symptomatic or enlarging lesions, and bevacizumab increasingly utilized as either a primary or adjunctive systemic option. Radiation therapy, by contrast, is employed selectively given its potential to compromise auditory function and its association with malignant transformation. Targeted agents such as bevacizumab (anti-VEGF), MEK inhibitors (selumetinib, trametinib), EGFR inhibitors (lapatinib, erlotinib), and mTOR inhibitors (everolimus) are examined across preclinical models and clinical trials. Emerging approaches including dual pathway inhibition and immunologic strategies such as VEGF receptor vaccination are also discussed. Importantly, NF2-VS exhibits molecular and clinical heterogeneity, with differing responses observed across pediatric and adult populations. Therapeutic limitations of current targeted therapies include resistance, toxicity, and the modest efficacy of monotherapies. As such, future investigations must refine endpoints (e.g., hearing stabilization vs. tumor regression), optimize dosing strategies, and personalize therapy based on age, tumor biology, and clinical trajectory. This review highlights the translational challenges and opportunities that lie ahead in delivering clinically efficacious therapies specific to each patient.
2026-02-16 | A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation.
Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.
2026-01-29 | Malignant pleural mesothelioma in a young patient with neurofibromatosis 2 and acquired BAP1 loss: A case report
• We present a BAP1 mutant malignant pleura mesothelioma in a patient with NF2 • Somatic NF2 mutations are common in mesothelioma but not germline loss • Diagnosis was complicated by unusual presentation and non-diagnostic biopsies • We still observe response to dual immunotherapy 14 months after starting treatment Neurofibromatosis type 2 (NF2) is a rare genetic disorder resulting from germline loss of the NF2 tumor suppressor gene characterized by the development of multiple benign central nervous system tumors. Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the pleura. We present a 32-year-old male with NF2 diagnosed with MPM found to have acquired BAP1 loss. We present a 33-year-old male patient with previously known NF2 who was found to have BAP1 and NF2 mutant MPM. The patient denied history of asbestos exposure or chest radiation. He presented with a persistent cough and tachycardia for which he underwent a computed tomography angiogram of the chest which discovered pleural effusion and pleural nodules. After a complicated diagnostic course involving 2 negative biopsies, a 3rd surgical biopsy finally showed sarcomatoid MPM, and molecular testing revealed mutations in BAP1 and NF2 . The patient was initiated on dual checkpoint immunotherapy and has a durable response 14 months since treatment initiation. This is the first case reported, to our knowledge, for which an NF2 patient was diagnosed with MPM at a young age and without known traditional risk factors. Somatic mutations in NF2 are often observed in MPM, but germline NF2 loss is not classically associated with MPM. However, in the setting of concomitant acquired BAP1 loss, germline NF2 loss could predispose a patient to MPM. This case highlights the importance of better understanding how genetic variants in tumor suppressor genes influence cancer risk.
2024-06-18 | NFS-28. CLINICAL CHARACTERISTICS AND THERAPEUTIC INTERVENTIONS IN A CASE SERIES OF PEDIATRIC PATIENTS WITH VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2
Abstract BACKGROUND Pediatric neurofibromatosis type 2 (NF2) is an understudied genetic disorder with high incidence of tumors including vestibular schwannomas (VS) and meningiomas. Although predominately recognized as an adult disease, there is a shortage of comprehensive studies in pediatric NF2. This case series describes a large cohort of pediatric NF2 patients with VS and their disease management. METHODS Our study included 24 patients with initial symptoms of NF2 before age 19. The patients were treated at the Neurofibromatosis Clinic of The University of Texas MD Anderson Cancer Center between 1/1/2005-12/31/2023. Our analysis incorporated data from clinic notes, surgical reports, audiology reports, electromyography reports, pathology reports, and imaging studies. RESULTS Patients presented with NF2 at an age range from 18 months to 18 years (mean age 8.1 ± 5.2 years). Among the patients, 67% underwent surgical interventions, including auditory brainstem implants, cochlear implants, ventriculoperitoneal shunts, and/or craniotomies for tumor resection. Additionally, treatment in 21% of cases involved radiotherapy, employing stereotactic radiosurgery, intensity-modulated radiotherapy, and proton beam irradiation. Targeted therapies, including bevacizumab, lapatinib, everolimus, temsirolimus, brigatinib, or a combination thereof, were administered to eleven patients. The best exhibited response by most patients was stable disease for a median duration of 10 months, and clinical improvement/stabilization of the hearing loss. Most reported toxicities related to bevacizumab or temsirolimus. Overall, limited clinical improvement was observed within this cohort after interventions. CONCLUSION This study discusses the clinical presentation of pediatric NF2 with VS and highlights the need for effective therapeutic options to manage tumors and symptoms in this patient population. A notable research gap exists in pediatric NF2, compounded by the lack of preclinical models to study the disease. The absence of approved drugs underscores the necessity for more comprehensive studies to guide therapeutic strategies. Combination therapies may advance treatment approaches and achieve improved outcomes.
2024-06-03 | PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.
Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.
small molecules
2026-07-22 | Pilot Evaluation of Targets in Neurofibromatosis Type 2: Drug Potency and Viability Analysis by the S' Metric
A pilot investigatoin into NF2 disease drug discovery data in mouse high throughput screening data from CENIX. HSP90 drug molecules were demonstrated as promising while using multiple endpoints, and alternative interpretation methods for working with dose response curve data are presented.
2026-06-17 | Repurposing anti-retroviral drugs to treat NF2-related tumours: a protocol for a phase 0 trial (RETREAT).
To date, there is no proven licensed systemic treatment for neurofibromatosis type 2 (NF2)-related schwannomatosis patients. There is a need for more effective, less toxic treatments and, as a rare disease, NF2 is often overlooked in targeted drug development. Subcutaneous schwannomas of the skin (CS) are common in the NF2 population.This trial involves the repurposing of medications already licensed for HIV-ritonavir and lopinavir (Kaletra and Norvir)-that have been shown to reduce tumour growth by reducing cell proliferation in human schwannoma and meningioma tumour cell cultures. The safety and tolerability of these drugs are already known, so they are safe candidates to trial in NF2 patients. This trial is an open-label, phase 0 design. A maximum of 16 participants diagnosed with NF2-related schwannomatosis will be enrolled in this study. Treatment duration is 30 days, with a 30-day follow-up. Biopsies and blood samples will be collected to assess whether the drugs reach the tumours and to analyse the tumour-cell response. The primary outcome is pharmacodynamic response, defined as a statistically significant decrease in biomarker activity in CS biopsy samples at day 30. The sample size calculation is based on the tissue biomarker response. The study was approved by an Ethics Committee (West of Scotland Research Ethics Service (23/WS/0178)), the Health Research Authority (HRA), the Medicines and Healthcare products Regulatory Authority (MHRA) and each of the participating NHS Trust's Research and Development departments. Following analysis of trial data, the trial results will be written up for publication in a peer-reviewed scientific journal and will be disseminated at conferences. ISRCTN10422213.
2026-05-29 | Comprehensive characterization of spinal ependymomas in NF2-Schwannomatosis.
Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is the cystic rather than the solid component of the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches. This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing. Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst. These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.
2026-05-12 | Loss of EPB41L3: A Common Molecular Link in the Tumorigenesis of Neurofibromatosis Types 1 and 2
摘要 背景：神经纤维瘤病1型（NF1）和神经纤维瘤病2型（NF2）是源自施旺细胞的常染色体显性疾病，分别表现为良性和恶性肿瘤的发展。本研究探讨了肿瘤的遗传和蛋白质组特征。 方法：对15名NF1和NF2患者（NF1和NF2）患者进行了突变分析，采用桑格测序。采用TMT标记光谱法鉴定NF1和NF2样本及神经对照组之间的蛋白质组差异。分析了候选基因EPB41L3的杂合子（LOH）丧失情况。使用西方印迹法和/或免疫荧光技术评估肿瘤组织和细胞培养中的蛋白质表达。 结果：DNA测序显示神经纤维瘤病1型和2型患者中，NF1和NF2基因均频繁突变。与正常神经相比，RNA测序显示NF1患者共有159种蛋白质显著表达差异，NF2患者中180种蛋白表达差异。其中，11种蛋白在两种肿瘤类型中均常被上调，30种蛋白共同下调。值得注意的是，两类肿瘤中均一致发现EPB41L3显著下调，且主要局限于HEI193和NF1细胞培养的细胞质中。西方墨迹（WB）分析显示，两种肿瘤类型的下调与神经纤维素和Merlin的表达有关。EPB41L3的杂合性（LOH）丧失率在NF1患者中（60%）高于NF2患者（20%）。此外，EPB41L3的过度表达抑制了HSC增殖和细胞存活率，显著上调了Merlin和神经纤维素的表达;而EPB41L3敲低则显著增加HSC的增殖和存活率，并显著下调了Merlin和神经纤维素的表达。 结论：我们的数据为神经纤维瘤的常见分子机制提供了初步见解，暗示EPB41L3可能成为该肿瘤综合征的潜在治疗靶点。 关键词：神经纤维瘤病1型，神经纤维瘤病2型，突变，蛋白质组学，蛋白组学，EPB41L3，LOH
2026-03-28 | Emerging Molecular Insights and Therapeutic Directions in Neurofibromatosis Type 1 and NF2-Related Schwannomatosis.
Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel TβR1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care.
cell therapies
2026-06-23 | Audiologic Outcomes with Auditory Brainstem Implantation Including Successful Open Set Speech Perception with Bilateral Implantation
Background/Objectives: For patients with profound deafness resulting from auditory nerve pathology, as in Neurofibromatosis type 2, auditory brainstem implantation (ABI) can restore meaningful acoustic input. The literature reporting real-world results for ABI users is limited, especially regarding patients with bilateral implants. Here, we provide an updated report on the audiologic outcomes among all ABI patients treated at a tertiary institution, including high-performing bilateral ABI users. Methods: In this updated and expanded retrospective case series, audiologic outcomes were reviewed in sixteen consecutive patients who underwent ABI placement by a single neurosurgeon-neurotologist team at our center since 2018. Implantation in four of these patients was on their second side after having undergone first side implantation prior to receiving care at our hospital. Main outcome measures were sound awareness (sound-field threshold testing) and speech understanding (pattern perception, spondee, open-set speech testing). Results: Sound awareness was achieved in 100% of patients (16/16) using an average of 12 electrodes (range 7–20). Persistent non-auditory sensations were reported by 12.5% (2/16). Postoperative speech differentiation (with or without lip-reading) was experienced in 87.5% (14/16). Two second-sided ABI recipients experienced exceptional outcomes as high-performing outliers: one achieved 57% audio only and 86% audio + visual hearing in noise test (HINT) sentence scores; the second bilateral user scored 92% with auditory-only input. Conclusions: ABI represents a viable option for patients who are at risk of developing bilateral profound deafness resulting from auditory nerve disruption. Second sided device implantation is safe and has the potential to significantly improve auditory outcomes.
2026-01-01 | T-cell-targeted immunotherapy in neurofibromatosis type 2-related vestibular schwannoma: current evidence and future direction
gene, which encodes the tumour suppressor protein merlin. This leads to development of benign tumours within the nervous system, most notably vestibular schwannomas that form on the vestibulocochlear (eighth cranial) nerve. Whilst the merlin-regulated molecular mechanisms in neoplastic Schwann cells that underlie vestibular schwannoma formation and growth are increasingly understood, the role of the tumour-immune microenvironment-particularly T-cells-in influencing vestibular schwannoma pathology and the clinical trajectory of disease remain understudied. In this review, we outline fundamental principles of T-cell immunobiology and anti-tumour immunity and examine their relevance to neurofibromatosis type-2-related schwannomatosis-associated vestibular schwannoma. We describe how spatial and transcriptomic profiling of tumour-infiltrating lymphocytes have revealed hallmarks of T-cell exhaustion and immunoevasion within vestibular schwannoma tumours and the existence of myriad immunosuppressive mechanisms within the vestibular schwannoma microenvironment-including immune checkpoint ligand expression, immunosuppressive cytokines, regulatory immune subsets and metabolic constraints. We also review the key remaining biological prerequisites, such as T-cell dynamics, T-cell functional state and T-cell spatial context within the tumour microenvironment, that must be addressed before advanced T-cell-based strategies can be rationally developed for vestibular schwannoma.
2025-07-02 | Papilledema in NF2-related Schwannomatosis without Ventriculomegaly and Overt Intracranial Hypertension: A Case Series and Literature Review.
Neurofibromatosis 2-related schwannomatosis is a rare genetic disorder marked by the development of multiple central nervous system tumors and, occasionally, non-hydrocephalic intracranial hypertension. This report details two cases of papilledema in patients with neurofibromatosis 2-related schwannomatosis, characterized by normal ventricular morphology on Magnetic resonance imaging and refractory to conservative treatment. Both patients-a 23-year-old and a 31-year-old female-demonstrated complete resolution of papilledema and restoration of visual function following ventriculoperitoneal shunt placement. These cases underscore the critical role of early ventriculoperitoneal surgical intervention in mitigating vision loss and emphasize the necessity for rigorous clinical surveillance in this unique patient population.
2024-10-02 | Long-term analysis of ABI auditory performance in patients with neurofibromatosis type 2-related schwannomatosis.
This retrospective monocentric study aimed to evaluate long-term auditory brainstem implant (ABI) function in patients with neurofibromatosis type 2, and to investigate the prognostic factors for ABI use. Between 1997 and 2022, 27 patients with at least five years of follow-up underwent implantation with 32 ABIs. At 1- and 5-years post-implantation and at last follow-up, ABIs were classified as used or non-used and the size of the ipsilateral tumor was recorded. For patients who used their ABIs, we assessed speech perception (disyllabic words, MBAA sentences) in quiet conditions with the ABI only, by lip-reading (LR), and with a combination of the two (ABI + LR). Hearing improvement was calculated as Δ ABI = (ABI + LR)-LR scores. Predictive factors for ABI use were analyzed. One year post-implantation, 74% patients were ABI-users and 66% of the ABIs were used. Two of these patients were non-users at five years, and another two at last follow-up (14 ± 5.2 years); 54% of the patients were ABI-users at last follow-up. Δ ABI revealed a hearing improvement of 32-41% (disyllabic words) and 28-37% (MBAA sentences). Among 16 ABIs with at least LR improvement at 1-year post-implantation, 4 decreased their performance, coinciding with a large growing ipsilateral tumor in 3/4 ABIs. We identified no significant prognostic factors for ABI use. ABIs are indicated in case of bilateral deafness with a non-functional cochlear nerve. Half the patients with ABIs used their implants and auditory performance remained stable over time, except in cases of ipsilateral tumor growth.
2024-05-22 | Audiological Outcome of the Simultaneous Tumor Resection and Cochlear Implantation in Two Cases of Sporadic and Two Cases of Neurofibromatosis Type 2-Associated Intracochlear Schwannoma
Objectives: Simultaneous removal and cochlear implantation (CI) have been reported in intralabyrinthine and intracochlear schwannoma. A wide range of postoperative hearing outcomes have been reported after CI in these cases. This study evaluated the outcomes of performing a simultaneous resection of Schwannoma in cochlea and cochlear implantation (CI), aiming to assess the effectiveness of this combined surgical approach for hearing rehabilitation with CI. Methods: This retrospective case series was conducted at a tertiary care center. The study included four consecutive patients with profound sensorineural hearing loss due to a mass inside the cochlea. These patients underwent simultaneous single-sided CI and tumor resection performed by the same surgeon. Preoperative and postoperative audiological assessments were conducted to evaluate the patients' hearing outcomes before and after the surgical intervention. Results: Simultaneous CI with tumor resection was successful in all cases. Two of the four patients had a unilateral tumor, while the other two had a bilateral tumor with the involvement of the internal auditory canal and cerebellopontine angle (neurofibromatosis type 2 (NF2)). In two cases of unilateral tumor, aided free-field pure tone average (PTA) was 26 dB, and 46 dB hearing level (HL), and word recognition score (WRS) at 65 dB was 40% and 68%, respectively, 3 months after surgery. In two cases of tumor with NF2, aided free-field PTA was 36 dB and 60 dB HL, and both cases showed 0% WRS at 65 dB 3 months after surgery. Conclusions: Simultaneous schwannoma excision and CI in patients with Schwannoma inside cochlea are surgically practical and safe. Postoperatively, there was a notable improvement in hearing in cases of sporadic schwannoma, regardless of the type of CI used. However, there was 0% WRS in the two NF2 patients with a mass in the internal auditory canal.
other
2026-02-16 | AI-Driven Machine Learning and CRISPR Guide RNA Optimization for Precision Medicine in Neurofibromatosis
Neurofibromatosis types 1 and 2 (NF1/NF2) are genetically complex disorders with highly variable clinical outcomes and limited precision tools to guide individualized treatment.Current therapies, such as MEK inhibitors, show inconsistent efficacy across patients.There is a critical need for computational approaches that can stratify mutation severity and optimize genome-editing strategies for targeted intervention.To develop and validate an AI-powered precision medicine framework that integrates machine learning for NF1/NF2 mutation classification and disease severity prediction, and deep-learningdriven CRISPR guide RNA (gRNA) optimization to enhance genomeediting accuracy and reduce off-target effects.This was a cross-sectional computational study using public genomic datasets and supervised machine learning models.Deep learning was applied for gRNA scoring.The study was conducted from 2023-2024 and included the development of a web-based deployment tool for real-time analysis.Data analysis and modeling were performed using publicly available databases and Python-based machine learning environments.A Streamlit-hosted web interface was created for realtime clinical and research use.NF1 and NF2 mutation records were curated from ClinVar, HGMD, and LOVD, including over 500 annotated patientderived mutations.Pathogenicity scores were extracted from REVEL and PolyPhen-2.No live human or animal subjects were involved.The machine learning model achieved 93% accuracy for NF1/NF2 mutation classification and 92% precision in disease severity prediction.The deep-learning CRISPR optimization framework demonstrated 98% on-target specificity and a 72% reduction in predicted off-target activity.A web-based interface processed 500 simulated patient sequences with 97% concordance with known ClinVar.This study presents a scalable, AI-driven framework that accurately classifies neurofibromatosis mutations and optimizes CRISPR gRNA selection.The integration of genomic annotation, deep learning, and real-time interface deployment may significantly enhance personalized gene-editing strategies for NF1/NF2 patients.These tools represent a critical step toward translational precision medicine in hereditary tumor syndromes.
2025-08-20 | [Management of Neurofibromatosis Type 2].
Surgical and radiotherapeutic interventions for vestibular schwannomas in patients with neurofibromatosis type 2 (NF2) generally yield less favorable outcomes than in sporadic unilateral cases, often hindering hearing preservation. Managing NF2 entails a lifelong series of complex decisions, repeatedly weighing functional preservation against impairment and surveillance against invasive therapeutic interventions. For both patients and their physicians, a critical issue lies in how to maximize functional preservation while simultaneously securing long-term survival. Auditory reconstruction using implantable auditory devices should be considered in cases of severe bilateral hearing loss. In patients with preserved cochlear nerve integrity, cochlear implantation is effective, and treatment strategies should be planned with this option in mind. Clinical trials of bevacizumab for pharmacological treatment are currently ongoing in Japan, and the clinical application of anti-vascular endothelial growth factor receptor vaccine therapy is anticipated.
2024-07-17 | Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.
The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.
2024-05-17 | Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions
Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.
2020-04-06 | A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2.
The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.
proteins
2026-04-10 | Single-cell and spatial transcriptomics analyses reveal tumor microenvironment-driven proliferation of NF2-associated vestibular schwannomas.
The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME among NF2-related schwannomatosis (NF2-SWN) patients with different clinical phenotypes, explore the reasons for these differences, and identify targets for treatment while gaining a deeper understanding of the pathogenesis of the disease. 20 vestibular schwannomas (VSs) from 20 clinically diagnosed NF2-SWN patients, including 11 milder patients (Gardner) and 9 severe patients (Wishart), were analyzed. Single-cell sequencing, TCR sequencing, spatial transcriptomics analysis, multiplex immunofluorescence, immunohistochemistry, and cell experiments were performed to compare the TME of Gardner and Wishart and to elucidate the mechanisms underlying these differences. Our results revealed that NF2-VS consist of 12 significant cell subpopulations, with Gardner and Wishart presenting distinct TME. Wishart exhibited more pronounced immune suppression. Conversely, CD8+ T cells from Gardner demonstrated potential for clonal proliferation. In macrophages, a subtype exhibited higher capacity of angiogenesis and high inflammatory cytokine activity was identified in Wishart, suggested its role in promoting tumor progression. Moreover, we found fibroblasts in Wishart showed excessive stromal deposition, potentially indicated the existence of immunologic barrier. Receptor‒ligand pair analysis revealed that Schwann cells in Wishart regulate immune cell activity via pleiotrophin (PTN), PTN positivity promotes anti-inflammatory cytokine activity, contributing to the formation of an immunosuppressive microenvironment to promote tumor progression. In summary, our study provides an in-depth analysis of the TME of NF2-VS, revealing the differences between Wishart and Gardner. Our study explains how Schwann cells influence the immune landscape to promote tumor development and clarifies the role of the TME in NF2-SWN progression, establishing a theoretical and experimental foundation for future immunotherapeutic strategies for NF2-SWN.
2023-02-28 | Merlin tumor suppressor function is regulated by PIP2-mediated dimerization.
Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. The NF2 gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region, and a C-terminal domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay to show that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus close to each other. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. Gel filtration experiments showed that dimerization occurs after a PIP2 mediated transition from closed to open conformation monomers. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
2015-06-05 | Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway
The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.
2012-04-19 | Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.
Neurofibromatosis type 2 (NF2) is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene. Patients with NF2 develop hallmark schwannomas that require surgery or radiation, both of which have significant adverse effects. Recent studies have indicated that the tumor microenvironment-in particular, tumor blood vessels-of schwannomas may be an important therapeutic target. Furthermore, although much has been done to understand how merlin, the NF2 gene product, functions as a tumor suppressor gene in schwannoma cells, the functional role of merlin in the tumor microenvironment and the mechanism(s) by which merlin regulates angiogenesis to support schwannoma growth is largely unexplored. Here we report that the expression of semaphorin 3F (SEMA3F) was specifically downregulated in schwannoma cells lacking merlin/NF2. When we reintroduced SEMA3F in schwannoma cells, we observed normalized tumor blood vessels, reduced tumor burden, and extended survival in nude mice bearing merlin-deficient brain tumors. Next, using chemical inhibitors and gene knockdown with RNA interference, we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1. This study shows that, in addition to the tumor-suppressing activity of merlin, it also functions to maintain physiological angiogenesis in the nervous system by regulating antiangiogenic factors such as SEMA3F. Restoring the relative balance of proangiogenic and antiangiogenic factors, such as increases in SEMA3F, in schwannoma microenvironment may represent a novel strategy to alleviate the clinical symptoms of NF2-related schwannomas.
2008-06-12 | Impaired intercellular adhesion and immature adherens junctions in merlin-deficient human primary schwannoma cells.
Schwannomas that occur spontaneously or in patients with neurofibromatosis Type 2, lack both alleles for the tumor suppressor and plasma membrane-cytoskeleton linker merlin. We have shown that human primary schwannoma cells display activation of the RhoGTPases Rac1 and Cdc42 which results in highly dynamic and ongoing protrusive activity like ruffling. Ruffling is an initial and temporally limited step in the formation of intercellular contacts like adherens junctions that are based on the cadherin-catenin system. We tested if there is a connection between Rac1-induced ongoing ruffling and the maintenance, stabilization and functionality of adherens junctions and if this is of relevance in human, merlin-deficient schwannoma cells. We show intense ongoing ruffling is not limited to membranes of single human primary schwannoma cells, but occurs also in membranes of contacting cells, even when confluent. Live cell imaging shows that newly formed contacts are released after a short time, suggesting disturbed formation or stabilization of adherens junctions. Morphology, high phospho-tyrosine levels and cortactin staining indicate that adherens junctions are immature in human primary schwannoma cells, whereas they display characteristics of mature adherens junctions in human primary Schwann cells. When merlin is reintroduced, human primary schwannoma cells show only initial ruffling in contacting cells and adherens junctions appear more mature. We therefore propose that ongoing Rac-induced ruffling causes immature adherens junctions and leads to impaired, nonfunctional intercellular adhesion in aggregation assays in merlin-deficient schwannoma cells that could be an explanation for increased proliferation rates due to loss of contact inhibition or tumor development in general.
antibodies
2026-05-17 | A review of targeted therapies for NF2-related vestibular schwannoma: molecular pathogenesis, emerging therapeutics, and future clinical horizons.
Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome driven by mutations in the NF2 gene. The mutation leads to aberrant proliferation of Schwann cells along the vestibular division of cranial nerve VIII, resulting in bilateral vestibular schwannomas (VS) that cause progressive hearing loss and neurological dysfunction. Loss of the tumor suppressor merlin results in dysregulation of multiple oncogenic pathways, including VEGF, MAPK/ERK, PI3K/AKT/mTOR, EGFR/ErbB, PDGFR, and Hippo-YAP. The inability of conventional management modalities to address the multifocal and progressive nature of NF2-associated tumors has driven investigation into targeted therapies. This review summarizes the evolving landscape of targeted therapies in NF2-associated vestibular schwannomas. Management of NF2-VS is individualized, with active surveillance favored for stable or smaller tumors, surgical resection pursued for symptomatic or enlarging lesions, and bevacizumab increasingly utilized as either a primary or adjunctive systemic option. Radiation therapy, by contrast, is employed selectively given its potential to compromise auditory function and its association with malignant transformation. Targeted agents such as bevacizumab (anti-VEGF), MEK inhibitors (selumetinib, trametinib), EGFR inhibitors (lapatinib, erlotinib), and mTOR inhibitors (everolimus) are examined across preclinical models and clinical trials. Emerging approaches including dual pathway inhibition and immunologic strategies such as VEGF receptor vaccination are also discussed. Importantly, NF2-VS exhibits molecular and clinical heterogeneity, with differing responses observed across pediatric and adult populations. Therapeutic limitations of current targeted therapies include resistance, toxicity, and the modest efficacy of monotherapies. As such, future investigations must refine endpoints (e.g., hearing stabilization vs. tumor regression), optimize dosing strategies, and personalize therapy based on age, tumor biology, and clinical trajectory. This review highlights the translational challenges and opportunities that lie ahead in delivering clinically efficacious therapies specific to each patient.
2026-02-16 | A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation.
Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.
2026-01-29 | Malignant pleural mesothelioma in a young patient with neurofibromatosis 2 and acquired BAP1 loss: A case report
• We present a BAP1 mutant malignant pleura mesothelioma in a patient with NF2 • Somatic NF2 mutations are common in mesothelioma but not germline loss • Diagnosis was complicated by unusual presentation and non-diagnostic biopsies • We still observe response to dual immunotherapy 14 months after starting treatment Neurofibromatosis type 2 (NF2) is a rare genetic disorder resulting from germline loss of the NF2 tumor suppressor gene characterized by the development of multiple benign central nervous system tumors. Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the pleura. We present a 32-year-old male with NF2 diagnosed with MPM found to have acquired BAP1 loss. We present a 33-year-old male patient with previously known NF2 who was found to have BAP1 and NF2 mutant MPM. The patient denied history of asbestos exposure or chest radiation. He presented with a persistent cough and tachycardia for which he underwent a computed tomography angiogram of the chest which discovered pleural effusion and pleural nodules. After a complicated diagnostic course involving 2 negative biopsies, a 3rd surgical biopsy finally showed sarcomatoid MPM, and molecular testing revealed mutations in BAP1 and NF2 . The patient was initiated on dual checkpoint immunotherapy and has a durable response 14 months since treatment initiation. This is the first case reported, to our knowledge, for which an NF2 patient was diagnosed with MPM at a young age and without known traditional risk factors. Somatic mutations in NF2 are often observed in MPM, but germline NF2 loss is not classically associated with MPM. However, in the setting of concomitant acquired BAP1 loss, germline NF2 loss could predispose a patient to MPM. This case highlights the importance of better understanding how genetic variants in tumor suppressor genes influence cancer risk.
2024-06-18 | NFS-28. CLINICAL CHARACTERISTICS AND THERAPEUTIC INTERVENTIONS IN A CASE SERIES OF PEDIATRIC PATIENTS WITH VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2
Abstract BACKGROUND Pediatric neurofibromatosis type 2 (NF2) is an understudied genetic disorder with high incidence of tumors including vestibular schwannomas (VS) and meningiomas. Although predominately recognized as an adult disease, there is a shortage of comprehensive studies in pediatric NF2. This case series describes a large cohort of pediatric NF2 patients with VS and their disease management. METHODS Our study included 24 patients with initial symptoms of NF2 before age 19. The patients were treated at the Neurofibromatosis Clinic of The University of Texas MD Anderson Cancer Center between 1/1/2005-12/31/2023. Our analysis incorporated data from clinic notes, surgical reports, audiology reports, electromyography reports, pathology reports, and imaging studies. RESULTS Patients presented with NF2 at an age range from 18 months to 18 years (mean age 8.1 ± 5.2 years). Among the patients, 67% underwent surgical interventions, including auditory brainstem implants, cochlear implants, ventriculoperitoneal shunts, and/or craniotomies for tumor resection. Additionally, treatment in 21% of cases involved radiotherapy, employing stereotactic radiosurgery, intensity-modulated radiotherapy, and proton beam irradiation. Targeted therapies, including bevacizumab, lapatinib, everolimus, temsirolimus, brigatinib, or a combination thereof, were administered to eleven patients. The best exhibited response by most patients was stable disease for a median duration of 10 months, and clinical improvement/stabilization of the hearing loss. Most reported toxicities related to bevacizumab or temsirolimus. Overall, limited clinical improvement was observed within this cohort after interventions. CONCLUSION This study discusses the clinical presentation of pediatric NF2 with VS and highlights the need for effective therapeutic options to manage tumors and symptoms in this patient population. A notable research gap exists in pediatric NF2, compounded by the lack of preclinical models to study the disease. The absence of approved drugs underscores the necessity for more comprehensive studies to guide therapeutic strategies. Combination therapies may advance treatment approaches and achieve improved outcomes.
2024-06-03 | PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.
Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.
small molecules
2026-07-22 | Pilot Evaluation of Targets in Neurofibromatosis Type 2: Drug Potency and Viability Analysis by the S' Metric
A pilot investigatoin into NF2 disease drug discovery data in mouse high throughput screening data from CENIX. HSP90 drug molecules were demonstrated as promising while using multiple endpoints, and alternative interpretation methods for working with dose response curve data are presented.
2026-06-17 | Repurposing anti-retroviral drugs to treat NF2-related tumours: a protocol for a phase 0 trial (RETREAT).
To date, there is no proven licensed systemic treatment for neurofibromatosis type 2 (NF2)-related schwannomatosis patients. There is a need for more effective, less toxic treatments and, as a rare disease, NF2 is often overlooked in targeted drug development. Subcutaneous schwannomas of the skin (CS) are common in the NF2 population.This trial involves the repurposing of medications already licensed for HIV-ritonavir and lopinavir (Kaletra and Norvir)-that have been shown to reduce tumour growth by reducing cell proliferation in human schwannoma and meningioma tumour cell cultures. The safety and tolerability of these drugs are already known, so they are safe candidates to trial in NF2 patients. This trial is an open-label, phase 0 design. A maximum of 16 participants diagnosed with NF2-related schwannomatosis will be enrolled in this study. Treatment duration is 30 days, with a 30-day follow-up. Biopsies and blood samples will be collected to assess whether the drugs reach the tumours and to analyse the tumour-cell response. The primary outcome is pharmacodynamic response, defined as a statistically significant decrease in biomarker activity in CS biopsy samples at day 30. The sample size calculation is based on the tissue biomarker response. The study was approved by an Ethics Committee (West of Scotland Research Ethics Service (23/WS/0178)), the Health Research Authority (HRA), the Medicines and Healthcare products Regulatory Authority (MHRA) and each of the participating NHS Trust's Research and Development departments. Following analysis of trial data, the trial results will be written up for publication in a peer-reviewed scientific journal and will be disseminated at conferences. ISRCTN10422213.
2026-05-29 | Comprehensive characterization of spinal ependymomas in NF2-Schwannomatosis.
Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is the cystic rather than the solid component of the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches. This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing. Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst. These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.
2026-05-12 | Loss of EPB41L3: A Common Molecular Link in the Tumorigenesis of Neurofibromatosis Types 1 and 2
摘要 背景：神经纤维瘤病1型（NF1）和神经纤维瘤病2型（NF2）是源自施旺细胞的常染色体显性疾病，分别表现为良性和恶性肿瘤的发展。本研究探讨了肿瘤的遗传和蛋白质组特征。 方法：对15名NF1和NF2患者（NF1和NF2）患者进行了突变分析，采用桑格测序。采用TMT标记光谱法鉴定NF1和NF2样本及神经对照组之间的蛋白质组差异。分析了候选基因EPB41L3的杂合子（LOH）丧失情况。使用西方印迹法和/或免疫荧光技术评估肿瘤组织和细胞培养中的蛋白质表达。 结果：DNA测序显示神经纤维瘤病1型和2型患者中，NF1和NF2基因均频繁突变。与正常神经相比，RNA测序显示NF1患者共有159种蛋白质显著表达差异，NF2患者中180种蛋白表达差异。其中，11种蛋白在两种肿瘤类型中均常被上调，30种蛋白共同下调。值得注意的是，两类肿瘤中均一致发现EPB41L3显著下调，且主要局限于HEI193和NF1细胞培养的细胞质中。西方墨迹（WB）分析显示，两种肿瘤类型的下调与神经纤维素和Merlin的表达有关。EPB41L3的杂合性（LOH）丧失率在NF1患者中（60%）高于NF2患者（20%）。此外，EPB41L3的过度表达抑制了HSC增殖和细胞存活率，显著上调了Merlin和神经纤维素的表达;而EPB41L3敲低则显著增加HSC的增殖和存活率，并显著下调了Merlin和神经纤维素的表达。 结论：我们的数据为神经纤维瘤的常见分子机制提供了初步见解，暗示EPB41L3可能成为该肿瘤综合征的潜在治疗靶点。 关键词：神经纤维瘤病1型，神经纤维瘤病2型，突变，蛋白质组学，蛋白组学，EPB41L3，LOH
2026-03-28 | Emerging Molecular Insights and Therapeutic Directions in Neurofibromatosis Type 1 and NF2-Related Schwannomatosis.
Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel TβR1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care.
cell therapies
2026-06-23 | Audiologic Outcomes with Auditory Brainstem Implantation Including Successful Open Set Speech Perception with Bilateral Implantation
Background/Objectives: For patients with profound deafness resulting from auditory nerve pathology, as in Neurofibromatosis type 2, auditory brainstem implantation (ABI) can restore meaningful acoustic input. The literature reporting real-world results for ABI users is limited, especially regarding patients with bilateral implants. Here, we provide an updated report on the audiologic outcomes among all ABI patients treated at a tertiary institution, including high-performing bilateral ABI users. Methods: In this updated and expanded retrospective case series, audiologic outcomes were reviewed in sixteen consecutive patients who underwent ABI placement by a single neurosurgeon-neurotologist team at our center since 2018. Implantation in four of these patients was on their second side after having undergone first side implantation prior to receiving care at our hospital. Main outcome measures were sound awareness (sound-field threshold testing) and speech understanding (pattern perception, spondee, open-set speech testing). Results: Sound awareness was achieved in 100% of patients (16/16) using an average of 12 electrodes (range 7–20). Persistent non-auditory sensations were reported by 12.5% (2/16). Postoperative speech differentiation (with or without lip-reading) was experienced in 87.5% (14/16). Two second-sided ABI recipients experienced exceptional outcomes as high-performing outliers: one achieved 57% audio only and 86% audio + visual hearing in noise test (HINT) sentence scores; the second bilateral user scored 92% with auditory-only input. Conclusions: ABI represents a viable option for patients who are at risk of developing bilateral profound deafness resulting from auditory nerve disruption. Second sided device implantation is safe and has the potential to significantly improve auditory outcomes.
2026-01-01 | T-cell-targeted immunotherapy in neurofibromatosis type 2-related vestibular schwannoma: current evidence and future direction
gene, which encodes the tumour suppressor protein merlin. This leads to development of benign tumours within the nervous system, most notably vestibular schwannomas that form on the vestibulocochlear (eighth cranial) nerve. Whilst the merlin-regulated molecular mechanisms in neoplastic Schwann cells that underlie vestibular schwannoma formation and growth are increasingly understood, the role of the tumour-immune microenvironment-particularly T-cells-in influencing vestibular schwannoma pathology and the clinical trajectory of disease remain understudied. In this review, we outline fundamental principles of T-cell immunobiology and anti-tumour immunity and examine their relevance to neurofibromatosis type-2-related schwannomatosis-associated vestibular schwannoma. We describe how spatial and transcriptomic profiling of tumour-infiltrating lymphocytes have revealed hallmarks of T-cell exhaustion and immunoevasion within vestibular schwannoma tumours and the existence of myriad immunosuppressive mechanisms within the vestibular schwannoma microenvironment-including immune checkpoint ligand expression, immunosuppressive cytokines, regulatory immune subsets and metabolic constraints. We also review the key remaining biological prerequisites, such as T-cell dynamics, T-cell functional state and T-cell spatial context within the tumour microenvironment, that must be addressed before advanced T-cell-based strategies can be rationally developed for vestibular schwannoma.
2025-07-02 | Papilledema in NF2-related Schwannomatosis without Ventriculomegaly and Overt Intracranial Hypertension: A Case Series and Literature Review.
Neurofibromatosis 2-related schwannomatosis is a rare genetic disorder marked by the development of multiple central nervous system tumors and, occasionally, non-hydrocephalic intracranial hypertension. This report details two cases of papilledema in patients with neurofibromatosis 2-related schwannomatosis, characterized by normal ventricular morphology on Magnetic resonance imaging and refractory to conservative treatment. Both patients-a 23-year-old and a 31-year-old female-demonstrated complete resolution of papilledema and restoration of visual function following ventriculoperitoneal shunt placement. These cases underscore the critical role of early ventriculoperitoneal surgical intervention in mitigating vision loss and emphasize the necessity for rigorous clinical surveillance in this unique patient population.
2024-10-02 | Long-term analysis of ABI auditory performance in patients with neurofibromatosis type 2-related schwannomatosis.
This retrospective monocentric study aimed to evaluate long-term auditory brainstem implant (ABI) function in patients with neurofibromatosis type 2, and to investigate the prognostic factors for ABI use. Between 1997 and 2022, 27 patients with at least five years of follow-up underwent implantation with 32 ABIs. At 1- and 5-years post-implantation and at last follow-up, ABIs were classified as used or non-used and the size of the ipsilateral tumor was recorded. For patients who used their ABIs, we assessed speech perception (disyllabic words, MBAA sentences) in quiet conditions with the ABI only, by lip-reading (LR), and with a combination of the two (ABI + LR). Hearing improvement was calculated as Δ ABI = (ABI + LR)-LR scores. Predictive factors for ABI use were analyzed. One year post-implantation, 74% patients were ABI-users and 66% of the ABIs were used. Two of these patients were non-users at five years, and another two at last follow-up (14 ± 5.2 years); 54% of the patients were ABI-users at last follow-up. Δ ABI revealed a hearing improvement of 32-41% (disyllabic words) and 28-37% (MBAA sentences). Among 16 ABIs with at least LR improvement at 1-year post-implantation, 4 decreased their performance, coinciding with a large growing ipsilateral tumor in 3/4 ABIs. We identified no significant prognostic factors for ABI use. ABIs are indicated in case of bilateral deafness with a non-functional cochlear nerve. Half the patients with ABIs used their implants and auditory performance remained stable over time, except in cases of ipsilateral tumor growth.
2024-05-22 | Audiological Outcome of the Simultaneous Tumor Resection and Cochlear Implantation in Two Cases of Sporadic and Two Cases of Neurofibromatosis Type 2-Associated Intracochlear Schwannoma
Objectives: Simultaneous removal and cochlear implantation (CI) have been reported in intralabyrinthine and intracochlear schwannoma. A wide range of postoperative hearing outcomes have been reported after CI in these cases. This study evaluated the outcomes of performing a simultaneous resection of Schwannoma in cochlea and cochlear implantation (CI), aiming to assess the effectiveness of this combined surgical approach for hearing rehabilitation with CI. Methods: This retrospective case series was conducted at a tertiary care center. The study included four consecutive patients with profound sensorineural hearing loss due to a mass inside the cochlea. These patients underwent simultaneous single-sided CI and tumor resection performed by the same surgeon. Preoperative and postoperative audiological assessments were conducted to evaluate the patients' hearing outcomes before and after the surgical intervention. Results: Simultaneous CI with tumor resection was successful in all cases. Two of the four patients had a unilateral tumor, while the other two had a bilateral tumor with the involvement of the internal auditory canal and cerebellopontine angle (neurofibromatosis type 2 (NF2)). In two cases of unilateral tumor, aided free-field pure tone average (PTA) was 26 dB, and 46 dB hearing level (HL), and word recognition score (WRS) at 65 dB was 40% and 68%, respectively, 3 months after surgery. In two cases of tumor with NF2, aided free-field PTA was 36 dB and 60 dB HL, and both cases showed 0% WRS at 65 dB 3 months after surgery. Conclusions: Simultaneous schwannoma excision and CI in patients with Schwannoma inside cochlea are surgically practical and safe. Postoperatively, there was a notable improvement in hearing in cases of sporadic schwannoma, regardless of the type of CI used. However, there was 0% WRS in the two NF2 patients with a mass in the internal auditory canal.
other
2026-02-16 | AI-Driven Machine Learning and CRISPR Guide RNA Optimization for Precision Medicine in Neurofibromatosis
Neurofibromatosis types 1 and 2 (NF1/NF2) are genetically complex disorders with highly variable clinical outcomes and limited precision tools to guide individualized treatment.Current therapies, such as MEK inhibitors, show inconsistent efficacy across patients.There is a critical need for computational approaches that can stratify mutation severity and optimize genome-editing strategies for targeted intervention.To develop and validate an AI-powered precision medicine framework that integrates machine learning for NF1/NF2 mutation classification and disease severity prediction, and deep-learningdriven CRISPR guide RNA (gRNA) optimization to enhance genomeediting accuracy and reduce off-target effects.This was a cross-sectional computational study using public genomic datasets and supervised machine learning models.Deep learning was applied for gRNA scoring.The study was conducted from 2023-2024 and included the development of a web-based deployment tool for real-time analysis.Data analysis and modeling were performed using publicly available databases and Python-based machine learning environments.A Streamlit-hosted web interface was created for realtime clinical and research use.NF1 and NF2 mutation records were curated from ClinVar, HGMD, and LOVD, including over 500 annotated patientderived mutations.Pathogenicity scores were extracted from REVEL and PolyPhen-2.No live human or animal subjects were involved.The machine learning model achieved 93% accuracy for NF1/NF2 mutation classification and 92% precision in disease severity prediction.The deep-learning CRISPR optimization framework demonstrated 98% on-target specificity and a 72% reduction in predicted off-target activity.A web-based interface processed 500 simulated patient sequences with 97% concordance with known ClinVar.This study presents a scalable, AI-driven framework that accurately classifies neurofibromatosis mutations and optimizes CRISPR gRNA selection.The integration of genomic annotation, deep learning, and real-time interface deployment may significantly enhance personalized gene-editing strategies for NF1/NF2 patients.These tools represent a critical step toward translational precision medicine in hereditary tumor syndromes.
2025-08-20 | [Management of Neurofibromatosis Type 2].
Surgical and radiotherapeutic interventions for vestibular schwannomas in patients with neurofibromatosis type 2 (NF2) generally yield less favorable outcomes than in sporadic unilateral cases, often hindering hearing preservation. Managing NF2 entails a lifelong series of complex decisions, repeatedly weighing functional preservation against impairment and surveillance against invasive therapeutic interventions. For both patients and their physicians, a critical issue lies in how to maximize functional preservation while simultaneously securing long-term survival. Auditory reconstruction using implantable auditory devices should be considered in cases of severe bilateral hearing loss. In patients with preserved cochlear nerve integrity, cochlear implantation is effective, and treatment strategies should be planned with this option in mind. Clinical trials of bevacizumab for pharmacological treatment are currently ongoing in Japan, and the clinical application of anti-vascular endothelial growth factor receptor vaccine therapy is anticipated.
2024-07-17 | Phase I/II Study of a Vascular Endothelial Growth Factor Receptor Vaccine in Patients With NF2-Related Schwannomatosis.
The humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184). VEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response. Sixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas. This study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.
2024-05-17 | Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions
Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.
2020-04-06 | A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2.
The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.
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Drug Discovery Landscape
6 orphan drug designations for Full NF2-related schwannomatosis.
6 orphan drug designations for Full NF2-related schwannomatosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Non-replicating recombinant adeno-associated virus carrying the human neurofibromin 2 (NF2) transgene (scAAV9.P400.NF2) | gene therapies | FDA | 2026-07-14 | — | Nationwide Children’s Hospital |
4-(4-(2-(Diethylamino)ethoxy)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-amine | small molecules | EMA | 2024-12-13 | — | Opis S.r.l. |
bevacizumab | antibodies | FDA | 2024-07-15 | — | DELBERT SAS |
Trineumin | small molecules | FDA | 2023-01-09 | — | PRG S&T Co., Ltd |
bortezomib | small molecules | FDA | 2016-07-05 | — | BioXcel Corporation |
N-hydroxy-4-(3-methyl-2-(S)phenyl-butyrylamino)benzamide | small molecules | EMA | 2012-04-26 | — | Propharma Group The Netherlands B.V. |
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