Referenced Papers

Abstract

Background: In decentralized clinical trials, some or all activities occur outside of traditional sites, which may reduce time away from school/work and decrease participation burden for patients and their parents/caregivers. This methodology may improve recruitment and retention in studies, which is important for rare diseases like neurofibromatosis type 1 (NF1) and schwannomatosis (SWN). Published guidance exists for the general conduct of decentralized trials, but specific considerations for clinical trial design and endpoints in NF1/SWN have not yet been explored. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration is a group of researchers, clinicians, and people affected by NF1 and SWN whose shared goal is to advance clinical trial methodology for NF1/SWN. In December 2023, REiNS members met to discuss the opportunities and challenges of conducting NF1/SWN decentralized trials. Results: Endpoints that are promising for use in NF1/SWN decentralized trials include visual acuity (as tested by the computerized amblyopia treatment study HOTV testing algorithm); electronic versions of REiNS-recommended patient-reported outcome measures; digital health technologies for functional outcomes; radiography and computed tomography scans for imaging outcomes; remote photography to assess cutaneous neurofibromas; "e-centralized" evaluations of neurocognitive functioning; and remote biomarkers collected with analyte stabilizing tubes and self-collection devices. Conclusions: Further research is necessary to validate endpoints for decentralized trials for NF1/SWN and evaluate their feasibility. However, trial designs that incorporate decentralized elements hold considerable promise for rare diseases like NF1/SWN where patients encounter significant barriers to traditional clinical trial participation.

Abstract

Individuals with NF2-related schwannomatosis (NF2-SWN) experience a complex constellation of physical, emotional, and social symptoms that substantially impact quality of life (QoL). Although disease-specific patient-reported outcome measures are increasingly important for evaluating treatment benefit in clinical trials, existing NF2-SWN QoL measures have limitations in content coverage and sensitivity to change. This study describes the development and initial validation a new disease-specific QoL assessment - the Quality of Life Evaluation in NF2-related Schwannomatosis Trials (QUEST). Using a three-phase, mixed-methods approach, items were generated through concept elicitation interviews with individuals with NF2-SWN and clinicians, prioritized via patient survey data, and refined through iterative cognitive debriefing procedures. The resulting 21-item QUEST assesses the extent to which NF2-SWN has negatively impacted a person's daily life over the past seven days. Initial psychometric evaluation was conducted in an international sample of 174 individuals with NF2-SWN aged 15 years and older (117 women (67%), 158 White individuals (89%)). Exploratory factor analysis supported a four-factor structure, and the total score demonstrated excellent internal consistency and strong test–retest reliability. Evidence of construct validity was demonstrated through hypothesized associations with disease-specific, generic, and domain-specific QoL measures, as well as known-groups validity based on self-reported disease severity and number of prior surgeries. Incremental validity analyses indicated that QUEST explained unique variance beyond existing measures. Together, findings support the QUEST as a reliable and valid disease-specific QoL measure with strong content validity and feasibility for use as a clinical trial endpoint in NF2-SWN.

Abstract

Introduction: Neurofibromatosis 1 and schwannomatosis are characterized by potential lifelong morbidity and life-threatening complications. To date, however, diagnostic and predictive biomarkers are an unmet need in this patient population. The inclusion of biomarker discovery correlatives in neurofibromatosis 1/schwannomatosis clinical trials enables study of low-incidence disease. The implementation of a common data model would further enhance biomarker discovery by enabling effective concatenation of data from multiple studies. Methods: The REiNS biomarker working group reviewed published data on emerging trends in neurofibromatosis 1 and schwannomatosis biomarker research and developed recommendations in a series of consensus meetings. Results: Liquid biopsy has emerged as a promising assay for neurofibromatosis 1/schwannomatosis biomarker discovery and validation. The working group reviews recommendations for a range of biomarkers in clinical trials, NF1/schwannomatosis-specific data annotations, and common data models for data integration. Conclusion: These REiNS consensus guidelines are intended to provide best practices for the inclusion of biomarker studies in neurofibromatosis 1/schwannomatosis clinical trials, data and sample annotation, and to lay a framework for data harmonization and concatenation between trials.

Abstract

Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

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Editorial introduction to the third REiNS supplement to Neurology, covering 2020 recommendations from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration. Summarizes the expansion of REiNS working groups since the 2016 supplement and the acceleration of NF clinical trial activity following selumetinib's FDA approval in April 2020 for pediatric NF1-related plexiform neurofibromas — the first approved drug for any NF. The supplement introduced new REiNS working group output on cutaneous neurofibromas (measurement, biomarkers, patient perspectives), NF2-SWN hearing outcomes, social skills and neurocognitive endpoints in NF1, patient engagement methodology, biomarker measurement, and imaging of plexiform neurofibromas. Recommendations apply across NF1, NF2-related schwannomatosis, and schwannomatosis subtypes.

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REiNS patient-reported outcome (PRO) working group systematic review and recommendations for measuring quality of life (QoL) in clinical trials across all neurofibromatosis conditions, including NF1, NF2-related schwannomatosis (NF2-SWN), and schwannomatosis (SWN). The paper reviews existing self-report and parent-report PRO measures across multidimensional QoL domains relevant to NF trials — covering pain intensity, global health, disease-specific functional impact, and emotional wellbeing. For NF2-SWN, the Neurofibromatosis 2 Impact on Quality of Life scale (NFTI-QoL) is recommended as the primary disease-specific PRO. For SWN pain, the PROMIS Pain Intensity and Pain Interference scales are recommended. The recommendations establish a framework for endpoint selection in psychosocial and pharmacological trials across NF subtypes. Context: the paper was published in the same year as the first FDA-approved drug for NF, making standardized QoL measurement in subsequent trials critically important.

Abstract

Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson's disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. This study demonstrates that RIT1 differs from classical RAS in GTPase cycling — unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions but showed only modest effects on canonical signaling pathways (MAPK, PI3K/AKT, JNK) in HEK293T overexpression models. RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension, with the KRLK-containing region contributing to phosphatidylserine and phosphoinositide binding. In reconstituted liposome systems, galectin-3 and LZTR1, but not galectin-1, reduced GDP-loaded RIT interactions with liposomes, suggesting that accessory proteins influence membrane dynamics. SWN-relevant finding: LZTR1 directly reduces RIT1 and RIT2 membrane binding when the GTPases are in their GDP-loaded (inactive) state. LZTR1-related schwannomatosis is caused by loss-of-function LZTR1 variants. This paper provides biochemical evidence for how LZTR1 normally restrains RIT GTPases at the membrane — when LZTR1 is absent or non-functional, RIT1 and RIT2 remain membrane-associated longer, with potential downstream effects on RAS pathway activation. This membrane-regulation function of LZTR1 is distinct from (and additive to) its role as a CUL3-RING ubiquitin ligase adaptor.

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A scoping review of 391 studies published 2023–2025 reporting emerging candidate genes implicated in congenital heart disease (CHD), identifying 912 candidate genes across statistical genotype-CHD association studies, candidate gene case studies, and clinical reports without functional evidence. LZTR1 was among the most commonly reported genes (n=10 articles), appearing in both statistical genotype-CHD association studies (n=2) and clinical reports without functional evidence (n=8). RIT1 also appeared in CHD literature. Neither LZTR1 nor RIT1 are currently ClinGen-curated for CHD. SWN-relevant context: LZTR1 is a schwannomatosis causative gene. Its repeated appearance in CHD genetics literature reflects primarily its role in Noonan syndrome 10 (OMIM #616564), where LZTR1 pathogenic variants cause congenital cardiac defects including pulmonary stenosis and HCM. Clinicians managing LZTR1-positive patients should be aware that LZTR1 has documented cardiac associations through the Noonan spectrum — patients and families may warrant a cardiac history inquiry. Important caveat: the LZTR1-CHD literature likely reflects Noonan syndrome cohorts, not schwannomatosis cohorts specifically. Direct evidence for cardiac risk in LZTR1-SWN patients without Noonan features has not been established.

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This study investigates the mechanistic basis of schwannomatosis-associated pain and identifies a dual therapeutic target addressing both pain and tumor growth simultaneously. Using patient-derived cell lines and xenograft models calibrated to reflect varying clinical pain levels, the authors developed a novel imaging approach for dorsal root ganglia (DRG) — the nerve clusters where nociceptive signals originate. Key mechanistic finding: Schwannomas at a distance from the DRG trigger macrophage infiltration into the tumor microenvironment; these tumor-associated macrophages produce excessive IL-6, which drives peripheral sensitization and pain. This establishes the Schwannoma → Macrophage → IL-6 → DRG Pain axis as a causal, not merely correlational, mechanism — and explains how SWN pain arises at sites remote from the tumor. Therapeutic finding: Anti-IL-6 antibodies reduced pain but did not arrest tumor growth; tumor cells activated EGFR signaling as an escape pathway. Dual blockade of IL-6 (pain pathway) and EGFR (tumor growth pathway) was required to simultaneously address both disease dimensions. This is the first study to demonstrate co-targeting of the pain and tumor compartments in a schwannomatosis model. — SWN relevance: Directly validates the patient experience that SWN pain does not require a tumor at the pain site; macrophage-mediated IL-6 release is the remote driver. IL-6 also upregulates Piezo2 in DRG neurons (Wan et al. 2024), connecting this macrophage pathway to the mechanosensitive ion channel research line. Authored by Plotkin (MGH) and Xu labs.

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Pre-clinical study using a schwannomatosis pain model to test whether GsMTx-4 — a peptide from tarantula venom (Grammostola spatulata) that blocks mechanosensitive ion channels (MSCs) — can reduce mechanical allodynia caused by schwannoma tumor secretions. Schwannoma cells were grown in culture; the resulting conditioned medium (CM) — a cocktail of tumor-secreted proinflammatory cytokines — was injected into a mouse hind paw to model schwannomatosis-related peripheral sensitization. A single CM injection reduced paw withdrawal threshold approximately 4-fold within one hour (p=0.006), with sensitization persisting at 48 hours (p=0.002). A neuronal priming model was also tested: a first CM exposure primed neurons such that a second CM injection produced hypersensitivity lasting up to 2 weeks (p<0.0001). GsMTx-4 (10 μM) prevented hypersensitivity when co-injected with CM, and reversed the primed hyperalgesic state to baseline (p<0.0001). The paper explicitly notes that "pain often preceding tumor detection" is a clinical hallmark of schwannomatosis, and that the MSC pathway explains pain arising before or without visible tumors. Funded by the CTF Drug Discovery Initiative. Contact: Kostrow3@jhmi.edu. Available online November 14, 2025. Open access CC BY-NC-ND 4.0.

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Comprehensive review of genetic contributors to schwannomatosis in patients who test negative for pathogenic variants in the three major genes (NF2, SMARCB1, LZTR1). A subset of affected individuals — including those with 22q loss of heterozygosity at the tumor level — remains without a definitive molecular diagnosis, limiting risk assessment, surveillance, and genetic counseling. Advances in sequencing technologies have enabled identification of novel candidate driver genes: SMARCA4 (SWI/SNF catalytic subunit), DGCR8 (microprocessor component at 22q11.2), and additional rarer candidates. The rarity of each finding makes establishing pathogenic relevance difficult; this review synthesizes current evidence and frames a research agenda for the gene-negative SWN population. Published Familial Cancer, November 2025. Full text paywalled.

Abstract

Sensation begins at the periphery, where distinct transducer proteins, activated by specific physical stimuli, initiate biological events to convert the stimulus into electrical activity. Mechanosensitive (MS) ion channels, which act as force transducers, have been found in organisms from archaea to mammals. This review covers the molecular basis of mechanosensitivity and emerging methods to investigate MS channels. Key findings relevant to SWN pain research: (1) GsMTx-4 (spider venom peptide from Grammostola spatulata) blocks currents through BOTH Piezo1 AND Piezo2 channels — confirmed by inhibiting Yoda1-induced Ca²⁺ influx, which can be produced by either channel subtype. (2) The Piezo membrane dome model: the Piezo channel protein deforms the surrounding membrane into a dome shape; when external tension forces the dome to flatten, the channel opens. GsMTx-4 works by altering local membrane curvature/tension, raising the threshold needed to force this conformational change. (3) Dooku1 is a Yoda1 antagonist — it binds the same allosteric pocket as Yoda1 (the Piezo1 agonist) but blocks the channel rather than opening it. (4) The two human Piezo genes (Piezo1 and Piezo2) account for the only identified MS channels in the human genome that are purely mechanically gated — highlighting the specificity of GsMTx-4 as a therapeutic target. (5) Pharmacological agents for Piezo channels remain limited and mostly nonspecific — no selective Piezo1-only or Piezo2-only inhibitor exists yet; GsMTx-4 is the most clinically studied.

Abstract — summary (full text paywalled)

This study investigated the role of Schwann cell (SC) Piezo1 in peripheral nociception using a novel AAV gene therapy approach. A new AAV vector (AAVolig001-CBA-GFP) was developed using the olig001 capsid — originally characterized for oligodendrocyte tropism after intracranial delivery — and validated for selective Schwann cell tropism after intraneural (sciatic or tibial nerve) injection. Six weeks post-injection in naive rats, GFP expression was detected selectively in both myelinating and non-myelinating Schwann cells. A dual-promoter bidirectional AAV (AAVolig001-PZ1shRNA) encoding a U6-driven short hairpin RNA against rat Piezo1 plus CBA-driven GFP was then injected into unilateral sciatic nerve immediately after common peroneal nerve injury (CPNI). Rats treated with AAVolig001-PZ1shRNA showed significantly mitigated development of mechanical hypersensitivity compared to scramble controls. Selective in vivo SC transduction and functional block of Piezo1 channel activity in primary cultured SCs was confirmed. Conclusions: (1) AAVolig001 has unique and selective primary tropism to Schwann cells via intraneural delivery; (2) Schwann cell Piezo1 is a functional contributor to mechanical hypersensitivity following nerve injury — silencing it in the Schwann cell compartment alone is sufficient to reduce nociception. — SWN relevance: This is direct causal evidence that Schwann cell Piezo1 mediates mechanical pain — not just correlation. The same Schwann cell population that forms schwannoma tumors uses Piezo1 to contribute to pain signaling. The AAV gene silencing approach demonstrated here is conceptually applicable to a schwannoma context, where tumor Schwann cells overexpressing or dysregulating Piezo1 could be selectively targeted. The olig001 capsid's SC tropism may offer a delivery mechanism relevant to future SWN gene therapy strategies. Institution: Medical College of Wisconsin (Hogan and Yu labs).

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Comprehensive clinical review of LZTR1- and SMARCB1-related schwannomatosis. Documents clinical characteristics (schwannomas predominantly on peripheral and spinal nerves, lumbar spine most common; meningiomas in SMARCB1 only; typical onset ages 20–40); diagnostic criteria requiring ≥2 non-intradermal schwannomas, absence of bilateral vestibular schwannomas, and identification of pathogenic germline variant; surveillance protocols including annual neurologic exam and MRI every 2–3 years from age 12; and the three-hit molecular mechanism (germline LZTR1/SMARCB1 mutation + 22q LOH + somatic NF2 inactivation). Penetrance estimated at 40–50%. Last revised December 4, 2025.

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Integrated analysis of bulk and single-cell genomics, biochemistry, and pharmacology across human tumor samples, cell lines, and mouse allografts to identify mechanisms by which NF tumor suppressors cooperate to drive Schwann cell malignant transformation and treatment resistance. Key finding: NF1 and NF2 loss function together — concurrent NF2 loss in NF1-mutant tumor cells drives de-differentiation toward a more primitive Schwann cell state and confers selumetinib (MEK inhibitor) resistance. DNA methylation subgroups of Schwann cell tumors correspond to differentiation programs that predict MEK inhibitor response. Functional genomic screening identified PAK kinase activation as the mechanism of MEK inhibitor escape — and demonstrated that concurrent MEK + PAK inhibition reversed resistance and was effective in vivo. Directly relevant to NF1 and NF2-SWN patients on selumetinib and other MEK inhibitor trials. Co-authored by Alyssa Reddy (UCSF), Frank McCormick (UCSF), and David Raleigh (UCSF).

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This study demonstrates that tumor-secreted extracellular vesicles (EVs) reprogram bone marrow-derived mesenchymal stem cells (MSCs) into a distinct inflammatory phenotype (iMSCs) that actively counteracts therapeutic response. Studied in multiple myeloma (MM) and osteosarcoma (OS), tumor-EVs triggered transcriptional reprogramming of MSCs toward pro-inflammatory, pro-tumor states via interferon-stimulated gene (ISG) activation and CXCL8 secretion. iMSCs in turn secreted signals that promoted tumor survival and therapy resistance. Key finding: Tumor-secreted EVs are not just local cytokine signals — they can stably reprogram stromal cells in the tumor microenvironment to become pro-tumor actors that resist treatment. This EV-mediated stromal reprogramming is a distinct mechanism from direct cytokine signaling. — SWN relevance: The Gutierrez 2025 (GsMTx-4 in schwannomatosis model) and Ostrow/Johns Hopkins work demonstrates that schwannoma cells secrete a cytokine cocktail — the "schwannoma-conditioned medium" — that sensitizes peripheral neurons. The Massaro paper extends the conceptual framework: if schwannoma-secreted EVs similarly reprogram surrounding stromal cells (Schwann cells, fibroblasts, immune cells) toward pro-tumor phenotypes, this could explain why the schwannoma microenvironment resists intervention even when individual cytokines are targeted. It also suggests that schwannoma EV cargo — not only secreted cytokines — may be a relevant target for both pain and tumor suppression. Filed here as background for the schwannoma secretome research line.

Abstract

Purpose of Review: Mechanosensitive Piezo channels are ion channels activated by mechanical stimuli, playing a crucial role in mechanotransduction processes and mechanical hypersensitivity. When these channels are subjected to mechanical loading, membrane currents rise instantaneously, depolarizing and activating voltage-gated calcium channels. This results in an increase in intracellular Ca²⁺, which contributes to heightened sensitivity to mechanical stimuli. This review delves into the characteristics and mechanisms of Piezo channels in chronic pain. Recent Findings: The findings suggest that Piezo channels are integral to the occurrence and development of chronic pain, including neuropathic pain, visceral pain, musculoskeletal pain, headache or orofacial pain, and inflammatory pain. Piezo channels significantly impact pain perception and transmission. These channels' critical involvement in various pain types highlights their potential as promising targets for chronic pain therapy. Summary: This review discusses the role of Piezo channels in chronic pain. By understanding these pain mechanisms, new therapeutic strategies can be developed to alleviate chronic pain. Key SWN-relevant findings: (1) Piezo1 is selectively expressed in 60% of rat DRG primary sensory neurons — with immunoreactivity also identified in Schwann cells surrounding axons in the sciatic nerve. Selective RNAi silencing of Schwann cell Piezo1 reduced mechanical hypersensitivity after peripheral nerve injury (Itson-Zoske et al. 2023). (2) Piezo2 is required for the development of tactile allodynia — the pathway responsible for pain from light touch. (3) GsMTx4 blocks both Piezo1 and Piezo2 by altering membrane curvature. (4) IL-6 upregulates Piezo2 in nerve injury models; inhibiting Piezo2 with GsMTx4 reversed dynamic allodynia and hyperalgesia — suggesting the IL-6 → Piezo2 axis as a mechanism through which anti-IL-6 therapy (siltuximab, STARFISH trial) may reduce allodynia. (5) Inflammatory cytokines (IL-1α, IL-6) sensitize Piezo channels in non-neuronal cells — consistent with the Gutierrez 2026 finding that tumor-secreted cytokines activate MSCs in schwannomatosis.

Abstract

The cation channel Piezo1, a crucial mechanotransducer found in various organs and tissues, has gained considerable attention as a therapeutic target in recent years. Following this trend, several Piezo1 inhibitors have been discovered and studied for potential pharmacological properties. This review provides an overview of the structural and functional importance of Piezo1, as well as discussing the biological activities of Piezo1 inhibitors based on their mechanism of action. The compounds addressed include the toxin GsMTx4, Aβ peptides, certain fatty acids, ruthenium red and gadolinium, Dooku1, as well as the natural products tubeimoside I, salvianolic acid B, jatrorrhizine, and escin. The findings revealed that misexpression of Piezo1 can be associated with a number of chronic diseases, including hypertension, cancer, and hemolytic anemia. Consequently, inhibiting Piezo1 and the subsequent calcium influx can have beneficial effects on various pathological processes, as shown by many in vitro and in vivo studies. However, the development of Piezo1 inhibitors is still in its beginnings, with many opportunities and challenges remaining to be explored.

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Segmental bone defects present clinical challenges requiring complex reconstruction strategies. This study addresses the hydrophobic nature of the Piezo1 agonist Yoda1 — which limits its delivery in hydrogel matrices — by employing Yoda1-pretreated bone marrow-derived mesenchymal stem cell (BMSC) exosomes (Exo-Yoda1). Exo-Yoda1-treated BMSCs demonstrated enhanced osteogenic capability versus controls, with similar functionality to Yoda1 itself. Transcriptome analysis revealed activation of osteogenesis-associated signaling pathways including phospho-ERK. Exo-Yoda1 integrated into GelMA/SAMA/β-TCP hydrogels augmented osteogenesis in subcutaneous ectopic models and rat skull bone defect models. The study confirms Piezo1/ERK as a Yoda1 signal transduction axis in bone repair. Note: directly relevant to SWN as confirming reference for Piezo1 downstream signaling biology; primary application is bone repair rather than schwannoma.

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Multicenter, prospective Phase II trial of maintenance bevacizumab in NF2-SWN patients with progressive vestibular schwannomas, following induction therapy. Patients received bevacizumab 5 mg/kg every 3 weeks for 18 months. Primary endpoints: hearing stability and tumor stability during the maintenance phase. Maintenance bevacizumab prevented hearing decline and tumor progression in the majority of participants with acceptable long-term tolerability. Provided the prospective evidence that long-term bevacizumab maintenance — not just induction — is a viable sustained treatment strategy for NF2-SWN vestibular schwannoma. Co-authored by Dhall (UAB NFCTC), Blakeley (Hopkins), Korf (UAB), Packer (Children's National), and Widemann (NCI), among other NFCN leaders.

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First report of SMARCA4-associated schwannomatosis. A proband presented with a spinal schwannoma at age 30; her mother had 4 peripheral schwannomas beginning at age 50, followed by a glioblastoma at age 54. Whole exome sequencing identified a likely pathogenic germline frameshift variant: SMARCA4 (NM_001128844.2):c.1752_1755del, p.(Lys585Argfs*27). This is the SMARCA4-specific SWN subtype — SMARCA4 encodes the catalytic ATPase subunit of the SWI/SNF chromatin-remodeling complex, paralogous to SMARCB1 (which encodes a structural subunit of the same complex). The SMARCA4 association explains a subset of schwannomatosis cases without NF2, SMARCB1, or LZTR1 mutations. Published as a Clinical Communication letter; epub February 14, 2023. Full text paywalled.

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The European Reference Network for Rare Tumour Syndromes (ERN GENTURIS) clinical practice guideline for schwannomatosis, developed using an enhanced GRADE approach tailored for rare disease research that integrates published evidence with expert clinical and patient perspectives. The guideline addresses diagnosis, treatment, management, and surveillance across all schwannomatosis subtypes. Published April 1, 2022 in the European Journal of Human Genetics. Available in 18 languages (English, German, French, Italian, Spanish, Polish, Dutch, Czech, Greek, Swedish, Portuguese, Hungarian, Danish, Norwegian, Lithuanian, Slovenian, Latvian, Estonian, Maltese) and in multiple formats: full guideline, peer-reviewed journal publication, pocket guide (clinical summary card), and plain language summary accessible to patients and non-specialists. Lead authors: Prof. D. Gareth Evans (Manchester, UK), Dr. Ignacio Blanco (Barcelona, Spain), Dr. Stefania Mostaccioli (Rome, Italy), on behalf of the ERN GENTURIS Schwannomatosis Guideline Group. ERN GENTURIS is one of 24 European Reference Networks funded by the European Commission to connect expert centers for patients with rare hereditary cancer predisposition syndromes.

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Review. Mesenchymal stromal/stem cells (MSCs) stimulate healing and reduce inflammation across many disease contexts, but clinical trial results have been inconsistent — inconsistencies attributed to differences in delivery route, product optimization, and background therapies. This review systematically examines the proposed mechanisms of action across different MSC delivery methods (local injection, intravenous, intrathecal, intraperitoneal, inhalation) and associated safety considerations. Key findings: (1) MSC therapeutic benefit appears most consistent with direct local delivery in specific disease states; (2) MSC paracrine activity — secreted factors, exosomes, and EVs — is the primary proposed mechanism, not engraftment; (3) Systemic delivery routes require navigating first-pass clearance and may reduce effective cell numbers reaching target tissue; (4) MSC secretome (cytokines, chemokines, growth factors, EVs) varies significantly by source tissue and preparation, contributing to inter-study variability. — SWN relevance: Background reference for understanding MSC biology in the context of the Massaro 2024 tumor EV/iMSC paper. MSCs are present in peripheral nerve tissue and tumor microenvironments; their behavior in response to tumor-secreted factors (including EVs) is directly relevant to understanding the schwannoma microenvironment. Also relevant to any future cell-based or EV-based therapeutic approaches targeting the schwannoma niche.

Abstract

The peripheral nervous system sustains constant mechanical constraints from developmental growth and movement. While YAP/TAZ mechanotransducers in Schwann cells have been studied, the role of mechanosensitive ion channels in myelinating Schwann cells was previously unexplored. This study comprehensively assessed all known mechanosensitive ion channels in Schwann cells and identified that PIEZO1 and PIEZO2 are among the most abundant mechanosensitive ion channels expressed, with Piezo1 showing the highest expression of any mechanosensitive channel tested. Key findings: **Expression:** Piezo1 (2−ΔCt: 11.57 ± 0.3) and Piezo2 (7.9 ± 0.71) were the top-ranking mechanosensitive ion channels in rat Schwann cells at 30 days, confirmed in mouse sciatic nerves by Western blot. Both proteins were elevated between P6–P15, the critical period of Schwann cell proliferation and myelination. **PIEZO1 → YAP/TAZ axis:** GsMTx4 (100 μM, 48h) reduced TAZ nuclear localization in Schwann cell cultures by 45.2% ± 3.8. Yoda1 (PIEZO1 agonist, 5 μM) increased TAZ nuclear enrichment +43.3% ± 8.1 at 60 min. This establishes a direct link between PIEZO1 mechanosensing and YAP/TAZ transcriptional activity — a pathway known to regulate Schwann cell development and implicated in tumorigenesis. **Conditional knockouts (Schwann cell-specific):** - Piezo1cKO: PIEZO1 is a transient inhibitor of myelination — its absence produced thicker myelin (P15), longer internodal lengths (large caliber fibers), and increased MBP/P0 protein levels. Also: reduced YAP activity, increased TAZ activity, increased ERK and AKT phosphorylation (+77.7% and +35.2%). - Piezo2cKO: PIEZO2 is required for myelin formation — its absence transiently delayed and reduced myelination (hypomyelination at P6 and P15). - Piezo1/2cKO: Double knockout phenotype mimics Piezo1cKO (enhanced myelination), not the sum of both — demonstrating an epistatic relationship in which PIEZO1 may act as an inhibitor of PIEZO2 during developmental myelination. **YAP activation and PIEZO1 activation (Yoda1) inhibits myelination:** Cocultures of Schwann cells + DRG neurons treated with Yoda1 produced fewer (−42%) and shorter (−14%) myelin segments versus controls. — SWN relevance: This is the first comprehensive demonstration that PIEZO1 and PIEZO2 are the dominant mechanosensitive ion channels in Schwann cells — the exact cell type that forms schwannoma tumors. PIEZO1 directly activates the YAP/TAZ pathway in Schwann cells; YAP/TAZ are established oncogenic drivers. If schwannoma mutations (SMARCB1, LZTR1, NF2) alter PIEZO channel activity or mechanosensitive thresholds in tumor Schwann cells, the downstream effects on YAP/TAZ and ERK/AKT could directly contribute to uncontrolled proliferation and tumor growth — independent of the pain pathway. GsMTx4 reduced PIEZO-driven TAZ activation by 45% in normal Schwann cells; this raises the question of whether it could modulate the oncogenic signaling cascade in tumor Schwann cells as well.

Abstract — summary (full text paywalled)

A multistep international consensus process — beginning with a Delphi method involving global disease experts, then incorporating non-neurofibromatosis clinical experts, patients, and patient advocacy organizations — produced updated diagnostic criteria for neurofibromatosis type 2 (NF2) and schwannomatosis (SWN). The consensus reached agreement on minimal clinical and genetic criteria for diagnosing NF2-related schwannomatosis (NF2-SWN) and all SWN subtypes, incorporating mosaic forms of each condition. Key outcomes: (1) NF2-related schwannomatosis was renamed NF2-SWN, placing it within the schwannomatosis family alongside SMARCB1-, LZTR1-, and gene-negative subtypes; (2) the term "neurofibromatosis type 2" was retired as a disease label (NF2 is preserved as the gene symbol); (3) the SWN-[GENE] nomenclature was standardized across all subtypes; (4) diagnostic criteria were updated to reflect genetic advances in LZTR1, SMARCB1, SMARCE1, and DGCR8. Note: full abstract paywalled. Summary compiled from published methodology descriptions and author statements.

Abstract — summary (full text paywalled)

A retrospective analysis of 97 patients with confirmed or probable schwannomatosis seen at two U.S. tertiary care NF clinics. The study documented the specific delays, diagnostic errors, and missed opportunities between first symptom onset and confirmed schwannomatosis diagnosis. Barriers identified included intermittent or non-specific initial symptoms, younger age at symptom onset, psychiatric misattribution of pain, pathology errors on individual tumor specimens, and failure to trigger genetics referrals after the first schwannoma. The study recommended interventions in clinician education, genetic testing availability, expert pathology review, and automatic referral triggers. Note: full abstract paywalled. Summary compiled from published preprint (medRxiv) and published paper findings. Free preprint available at medRxiv link above.

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International consensus revision of diagnostic criteria for neurofibromatosis type 1 (NF1), using the same multistep Delphi methodology as the 2022 SWN reclassification. Updated NF1 criteria incorporate new clinical features (whole-body MRI, deep plexiform neurofibromas, sphenoid wing dysplasia refinements) and expanded molecular diagnosis (heterozygous pathogenic NF1 variant by sequencing now meets criteria). Also established separate diagnostic criteria for Legius syndrome (SPRED1 pathogenic variants), which phenotypically overlaps with NF1 in young patients presenting with only café au lait spots. Co-authored by Korf, Gutmann, Plotkin, Blakeley, and virtually every major NF center director — this paper and the 2022 SWN consensus together are the current paired standard for NF1 and SWN diagnosis.

Abstract — summary (full text paywalled)

Multiplatform genomic analysis of schwannomatosis schwannomas across all molecular subtypes — including SMARCB1-mutant, LZTR1-mutant, NF2-mutant (schwannomatosis setting), and gene-negative tumors — using DNA methylation profiling, whole-genome sequencing, and RNA sequencing. Identified four distinct DNA methylation subgroups in schwannomatosis schwannomas, each associated with specific transcriptional programs and tumor location. Demonstrated that schwannomatosis schwannomas are epigenomically and transcriptomically distinct from sporadic schwannomas and NF2-associated schwannomas. Co-authored by Mansouri (then at Toronto/UHN, now Wilkins Family Chair), Plotkin, Blakeley, Korf, and Messiaen. This is the foundational multi-omic map of the schwannomatosis molecular landscape — cited in the 2022 consensus reclassification.

Abstract

Comprehensive preclinical validation of AAV/Olig001 in the nur7 mouse model of Canavan disease (congenital white matter disease caused by ASPA deficiency). Intracerebroventricular (ICV) infusion into CSF was identified as the optimal route of administration, achieving >70% oligotropism in all CNS regions of interest (except cerebellum) without lineage-specific promoters. AAV/Olig001-ASPA delivery resulted in dose-dependent rescue of ASPA enzyme activity, near-total reduction in vacuolation, and improved motor function. Head-to-head comparison with astrogliotropic AAV9 showed significant advantage for Olig001 that was independent of overall transduction efficiency — confirming that cell-type specificity confers therapeutic advantage beyond mere transduction numbers. Open access. Published March 2021. Institution: Rowan University School of Osteopathic Medicine / UT Southwestern / UNC Chapel Hill / Asklepios BioPharmaceutical. — SWN relevance: Establishes preclinical efficacy and biodistribution profile for AAV/Olig001 in a CNS white matter disease model. Directly relevant as supporting validation for the Itson-Zoske 2025 approach (intraneural AAV/Olig001 for Schwann cell Piezo1 silencing). This paper confirms that Olig001 can achieve therapeutically meaningful transduction efficiency in glial cells — the same cell lineage as Schwann cells — and documents its safety and distribution profile.

Abstract

BACKGROUND. DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist. METHODS. Whole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K–positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K. RESULTS. We identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons. CONCLUSION. We identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.

Abstract

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel's mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value.

Abstract

Review. Myelin sheath geometry — thickness relative to internodal length — is critical to optimize nerve conduction velocity in the peripheral nervous system, and these parameters are independently regulated by myelinating Schwann cells. This review examines the molecular mechanisms that govern mechanically-driven myelin sheath elongation, including the epithelial-like cell polarization process that occurs during early myelin biogenesis. Key mechanisms: (1) Internodal length is regulated by postnatal body growth, which physically elongates peripheral nerves — providing mechanical cues that the myelinating Schwann cell must detect and respond to. (2) Mechanical stretching of peripheral nerves in adult animals directly increases myelin sheath length, demonstrating that Schwann cells respond to physical force during adult life, not only during development. (3) YAP/TAZ co-transcription factors play critical roles during Schwann cell myelination, with their function linked to mechanotransduction through the Hippo pathway and the epithelial polarity factor Crb3. PIEZO channels are discussed as upstream mechanosensors. — SWN relevance: This foundational review establishes that myelinating Schwann cells are mechanosensitive, and that the YAP/TAZ/Hippo axis is the downstream effector of mechanical sensing in the Schwann cell lineage. NF2 (merlin) normally suppresses YAP/TAZ through the Hippo pathway; loss of merlin in schwannoma cells allows YAP/TAZ to run unchecked. PIEZO1 in Schwann cells directly activates TAZ nuclear localization (established by Itson-Zoske 2023/Acheta 2022); Tricaud establishes the broader context that this mechanosensitive control of YAP/TAZ is fundamental to normal Schwann cell biology — and therefore that its dysregulation in schwannoma may drive tumorigenesis through a pathway that is mechanically, not only genetically, regulated.

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Multicenter Phase II trial evaluating bevacizumab for hearing loss in NF2-SWN patients with progressive vestibular schwannomas, with prospective biomarker collection. 22 patients enrolled across multiple NFCN centers; 14 evaluable for the primary hearing endpoint. The primary hearing response (≥10-word improvement in word recognition score) was achieved in 57% of evaluable patients. Volumetric tumor response (≥20% decrease) in 55%. Established the 57% hearing response rate as the reference benchmark for bevacizumab in NF2-SWN. Biomarker analysis identified circulating plasma VEGF and placental growth factor as potential predictors of response — the first biomarker data for bevacizumab in NF2-SWN. This paper is the primary reference for the 57% hearing improvement statistic cited in NF center descriptions.

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No AAV capsid had previously been described with primary oligodendrocyte tropism under a constitutive promoter — a barrier for efficient oligodendrocyte gene transfer in vivo. A novel capsid, Olig001, was generated by capsid shuffling and directed evolution. Olig001 contains a chimeric mixture of AAV1, 2, 6, 8, and 9, but exhibits >95% tropism for striatal oligodendrocytes after rat intracranial infusion. Unlike parental serotypes, Olig001 has very low affinity for peripheral organs (especially liver) after intravenous administration. In mixed glial cell cultures, Olig001 exhibited 9-fold greater binding compared to AAV8. — SWN relevance: Olig001 is the foundational delivery vector used by Itson-Zoske et al. (2025) for selective Schwann cell transduction via intraneural injection — achieving the first in vivo RNAi silencing of Schwann cell Piezo1 and demonstrating reduced mechanical hypersensitivity after nerve injury. This paper establishes Olig001's original characterization. Note that Olig001 was initially designed for oligodendrocytes; its Schwann cell tropism via intraneural delivery was discovered separately (see Itson-Zoske 2025) and represents a second tropism that has direct implications for schwannoma gene therapy targeting.

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Sequenced germline DNA from additional schwannomatosis patients lacking SMARCB1 and NF2 mutations. Identified 18 novel LZTR1 variants across an expanded cohort. Found LZTR1 pathogenic variants in 43% of familial schwannomatosis cases and 30% of sporadic cases lacking SMARCB1 mutations — extending the original Piotrowski 2014 LZTR1 discovery to a broader population and substantially defining the expected detection rates in clinical genetic testing. Co-authored by Laura Papi (University of Florence), one of the primary European researchers in SWN genetics.

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Sequenced germline DNA from 20 probands with schwannomatosis lacking pathogenic SMARCB1 or NF2 mutations. Identified 15 different germline heterozygous loss-of-function mutations in the LZTR1 gene in 16 of 20 probands — including 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. Established LZTR1 (leucine-zipper-like transcriptional regulator 1) as a tumor suppressor on chromosome 22q11 that predisposes to an autosomal dominant inherited disorder of multiple schwannomas. This was the first identification of LZTR1 as a schwannomatosis predisposition gene — opening the door to a distinct SWN-LZTR1 subtype separate from SMARCB1 and NF2.

Abstract

Diarthrodial joints are essential for load bearing and locomotion. Chondrocytes regulate their metabolic activities in response to mechanical loading; pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. This study identifies Piezo1 and Piezo2 as the mechanosensitive ion channels responsible for high-strain mechanotransduction in articular chondrocytes. Key finding — Piezo1/2 synergy: Coexpression of both Piezo1 and Piezo2 produced mechanically induced Ca²⁺ signals and electrical currents far exceeding either channel alone. In N2A cells cotransfected with both channels, AFM compression produced Ca²⁺ peaks of ~588 nM lasting ~22 seconds. Single-channel expression produced signals reduced to <10% of that level (ΔCa²⁺ ≤52 nM). Electrophysiology confirmed: cotransfected cells showed 2× higher peak currents and 6× higher plateau currents versus single Piezo expression. GsMTx4 as Piezo1/2 blocker: GsMTx4 inhibited AFM-evoked Ca²⁺ responses in primary chondrocytes in a dose-dependent, fully reversible manner. At 40 μM it was equipotent to extracellular Ca²⁺ removal. The D-enantiomer of GsMTx4 was used, confirming the membrane curvature (not chiral) mechanism. Dynasore potentiation: Co-application of the dynamin GTPase inhibitor dynasore (5 μM) with low-dose GsMTx4 (2 μM — ineffective alone) fully inhibited the channels — a 20-fold reduction in effective KD. Mechanism: dynasore reduces membrane curvature remodeling by dynamin, allowing GsMTx4 to insert at the channel–lipid interface more efficiently. Cartilage injury model: GsMTx4 pretreatment (40 μM) significantly reduced the "zone of death" surrounding mechanical biopsy wounds in osteochondral explants (P < 0.005). This establishes GsMTx4 as a tissue-protective agent against Piezo-mediated mechanotransduction injury — not merely a pain signal blocker. Both Piezo1 and Piezo2 were confirmed expressed in mouse, porcine, and human articular chondrocytes by RT-qPCR and immunostaining. — SWN relevance: This foundational paper establishes the Piezo1/2 synergy principle in non-neural mechanosensitive cells. In schwannomatosis, Piezo1 is expressed in Schwann cells (the tumor cells themselves; Itson-Zoske et al. 2023) and Piezo2 is upregulated in DRG neurons via IL-6 (Liu et al. 2021; Wan et al. 2024). If both channels are simultaneously active — Piezo1 in tumor tissue and Piezo2 in adjacent neurons — the synergistic amplification shown here predicts dramatically amplified pain signals disproportionate to tumor burden. GsMTx4 blocks both channels via the same membrane curvature mechanism, making it uniquely positioned to break the synergistic loop at its source.

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First prospective study demonstrating that bevacizumab (anti-VEGF antibody) can reduce vestibular schwannoma volume and improve hearing in patients with NF2-related schwannomatosis. 10 patients with progressive NF2-SWN received bevacizumab 5 mg/kg every 2 weeks. 9 of 10 patients had a volumetric radiographic response (≥15% reduction in tumor volume). Hearing improved in 8 of 10 patients; the improvement was rapid — occurring within the first few treatment cycles. This was the pivotal proof-of-concept that laid the groundwork for subsequent Phase II bevacizumab trials in NF2-SWN (Blakeley 2016, Plotkin 2023) and established anti-VEGF as the primary systemic treatment strategy for NF2-SWN vestibular schwannoma.