RARE DISEASE
Primary erythromelalgia
Primary erythromelalgia
Primary erythromelalgia
Synonyms: Primary erythermalgia
Synonyms: Primary erythermalgia
Synonyms: Primary erythermalgia
Drug discovery
9
drugs
With orphan designations
Overview
Primary erythromelalgia (EM) is a rare autosomal dominant neuropathy characterized by episodic burning pain, erythema, and warmth in acral regions, often triggered by heat or physical activity [1][4]. Linked to SCN9A gene mutations causing hyperexcitability of Nav1.7 sodium channels [6][16], it typically manifests in childhood or adolescence [6][16]. Diagnosis relies on clinical evaluation and genetic testing, with variable treatment responses and significant morbidity [1][7].
Therapies
Pharmacologic: Sodium channel blockers (mexiletine [1][6], lidocaine), venlafaxine [1][9], antihistamines [1][8], and topical agents (capsaicin, diclofenac) [3][8].
Non-pharmacologic: Cooling measures [13], avoidance of triggers [16].
Procedural: Sympathetic nerve blocks, spinal cord stimulators (refractory cases) [8][16].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
309 drug discovery papers about Primary erythromelalgia, with 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
309 drug discovery papers about Primary erythromelalgia, with 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2023-12-21 | Elucidating molecular mechanisms of protoxin-II state-specific binding to the human NaV1.7 channel
Human voltage-gated sodium (hNaV) channels are responsible for initiating and propagating action potentials in excitable cells, and mutations have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels are expressed in peripheral neurons and are promising targets for pain therapy. The tarantula venom peptide protoxin-II (PTx2) has high selectivity for hNaV1.7 and is a valuable scaffold for designing novel therapeutics to treat pain. Here, we used computational modeling to study the molecular mechanisms of the state-dependent binding of PTx2 to hNaV1.7 voltage-sensing domains (VSDs). Using Rosetta structural modeling methods, we constructed atomistic models of the hNaV1.7 VSD II and IV in the activated and deactivated states with docked PTx2. We then performed microsecond-long all-atom molecular dynamics (MD) simulations of the systems in hydrated lipid bilayers. Our simulations revealed that PTx2 binds most favorably to the deactivated VSD II and activated VSD IV. These state-specific interactions are mediated primarily by PTx2’s residues R22, K26, K27, K28, and W30 with VSD and the surrounding membrane lipids. Our work revealed important protein–protein and protein–lipid contacts that contribute to high-affinity state-dependent toxin interaction with the channel. The workflow presented will prove useful for designing novel peptides with improved selectivity and potency for more effective and safe treatment of pain.
2023-10-06 | A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.
Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM4-GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically approved drug varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Stable expression of the channel led to similar reversible suppression of pain-related behavior even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM4-GlyR activation in acute and joint pain inflammation mouse models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioral hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM4-GlyR activation decreased the excitability of human-induced pluripotent stem cell-derived sensory neurons and spontaneous activity due to a gain-of-function NaV1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable, and reversible humanized chemogenetic system for the treatment of pain.
2023-03-21 | Inhibition of sensory neuron driven acute, inflammatory, and neuropathic pain using a humanised chemogenetic system
Abstract Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM 4 -GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically-approved drug, varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally-mediated expression of PSAM 4 -GlyR in mouse sensory neurons produced behavioural hyposensitivity upon agonist administration, which was recovered upon agonist washout. Importantly, stable expression of the channel led to similar reversible behavioural effects even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM 4 -GlyR activation in acute and joint pain inflammation models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioural hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM 4 -GlyR activation decreased the excitability of human induced pluripotent stem-cell-derived sensory neurons and spontaneous activity due to a gain of function Na V 1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable and reversible human-based chemogenetic system for the treatment of pain.
2021-06-21 | Uncoupling sodium channel dimers restores the phenotype of a pain-linked Nav 1.7 channel mutation.
The voltage-gated sodium channel Nav 1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans. The hNav 1.7/A1632E channel mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage-gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav 1.7/A1632E mutation, and how dimerization modifies function of the pain-linked mutation. We applied atomistic molecular simulations to demonstrate the effect of the mutation on channel fast inactivation. Native PAGE was used to demonstrate channel dimerization, and electrophysiological measurements in HEK cells and Xenopus laevis oocytes were used to analyze the links between functional channel dimerization and impairment of fast inactivation by the hNav 1.7/A1632E mutation. Enhanced persistent current through hNav 1.7/A1632E channels was caused by impaired binding of the inactivation particle, which inhibits proper functioning of the recently proposed allosteric fast inactivation mechanism. hNav 1.7 channels form dimers and the disease-associated persistent current through hNav 1.7/A1632E channels depends on their functional dimerization status: Expression of the synthetic peptide difopein, a 14-3-3 inhibitor known to functionally uncouple dimers, decreased hNav 1.7/A1632E channel-induced persistent currents. Functional uncoupling of mutant hNav 1.7/A1632E channel dimers restored their defective allosteric fast inactivation mechanism. Our findings support the concept of sodium channel dimerization and reveal its potential relevance for human pain syndromes.
2021-01-28 | Spider Venom Peptide Pn3a Inhibition of Primary Afferent High Voltage-Activated Calcium Channels
Despite potently inhibiting the nociceptive voltage-gated sodium (Na v ) channel, Na v 1.7, µ -theraphotoxin Pn3a is antinociceptive only upon co-administration with sub-therapeutic opioid agonists, or by itself at doses >3,000-fold greater than its Na v 1.7 IC 50 by a yet undefined mechanism. Na v channels are structurally related to voltage-gated calcium (Ca v ) channels, Ca v 1 and Ca v 2. These channels mediate the high voltage-activated (HVA) calcium currents ( I Ca ) that orchestrate synaptic transmission in nociceptive dorsal root ganglion (DRG) neurons and are fine-tuned by opioid receptor (OR) activity. Using whole-cell patch clamp recording, we found that Pn3a (10 µM) inhibits ∼55% of rat DRG neuron HVA- I Ca and 60–80% of Ca v 1.2, Ca v 1.3, Ca v 2.1, and Ca v 2.2 mediated currents in HEK293 cells, with no inhibition of Ca v 2.3. As a major DRG I Ca component, Ca v 2.2 inhibition by Pn3a ( IC 50 = 3.71 ± 0.21 µM) arises from an 18 mV hyperpolarizing shift in the voltage dependence of inactivation. We observed that co-application of Pn3a and µ-OR agonist DAMGO results in enhanced HVA- I Ca inhibition in DRG neurons whereas co-application of Pn3a with the OR antagonist naloxone does not, underscoring HVA channels as shared targets of Pn3a and opioids. We provide evidence that Pn3a inhibits native and recombinant HVA Ca v s at previously reportedly antinociceptive concentrations in animal pain models. We show additive modulation of DRG HVA- I Ca by sequential application of low Pn3a doses and sub-therapeutic opioids ligands. We propose Pn3a's antinociceptive effects result, at least in part, from direct inhibition of HVA- I Ca at high Pn3a doses, or through additive inhibition by low Pn3a and mild OR activation.
small molecules
2026-09-08 | A Case of Refractory Erythromelalgia Treated Successfully with Suzetrigine, a Selective Sodium Channel Blocker
Background: Erythromelalgia is an uncommon neurovascular pain disorder characterized by episodic erythema, warmth, and burning pain, typically affecting the distal extremities. This condition can be debilitating and difficult to treat, often resulting in poor response to multiple therapies. Hereditary forms are often linked to mutations in the SCN9A gene, which encodes the NaV1.7 sodium channel, resulting in hyperexcitability of nociceptive neurons. Case Presentation: A 31-year-old male presented with a lifelong history of recurrent redness, warmth, and pain involving the bilateral hands and feet. Clinical diagnosis was based on characteristic symptoms and family history, notable for similar findings in his mother and children, suggesting a hereditary component. Multiple standard therapies provided minimal relief, including low-dose and high-dose aspirin, amitriptyline, doxepin, pregabalin, gabapentin, venlafaxine, colchicine, and compounded topical formulations containing amitriptyline, ketamine, and lidocaine. He was started on the non-opioid analgesic suzetrigine (Journavx) 50 mg daily, a novel selective NaV1.8 sodium channel blocker, by a pain specialist for off-label management of chronic low back pain. Within one month, he reported greater than 75% improvement in pain, erythema, and flare duration, along with significant improvement in quality of life. Discussion & Conclusion: This case highlights the potential of targeted sodium channel blockade in erythromelalgia. Although suzetrigine selectively inhibits NaV1.8, its downstream interaction with NaV1.7 in pain signal propagation suggests possible mechanistic overlap. In this patient with refractory erythromelalgia, treatment with suzetrigine was associated with meaningful improvement. Further studies are necessary to better characterize the efficacy and broader applicability of this alternative therapeutic approach.
2026-09-04 | Pain Management in Erythromelalgia: A Systematic Review and Graded Appraisal Across Etiological Subtypes.
Erythromelalgia is a rare disorder characterised by burning pain, erythema and increased skin temperature in the extremities. Its pathophysiological heterogeneity, together with variable treatment responses, complicates management in the absence of evidence-based guidelines. This systematic review appraised pain-management strategies across reported aetiological subtypes. Following PRISMA 2020 guidelines, the review was registered in PROSPERO (CRD420251232074). PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for studies published or registered between 1 January 2000 and 30 April 2026. Randomised controlled trials, non-randomised interventional studies, cohort studies and case series were eligible; non-randomised studies required at least five individuals. Risk of bias was assessed using Joanna Briggs Institute tools and certainty of evidence using GRADE. Of 3372 records, 25 studies reporting 591 individuals were included. Aetiological subtype was reported for 277 individuals (46.9%). Mechanistic and aetiological characterisation varied substantially across domains, with haematological data available for 72.6% and SCN9A status for 19.0% of the overall population. Moderate-certainty evidence supported aspirin in myeloproliferative neoplasm-associated erythromelalgia. Low-certainty evidence suggested benefit from mexiletine and carbamazepine in primary erythromelalgia, as well as from prostaglandin analogues, corticosteroids, selected topical therapies and sympathetic interventions in specific contexts. Evidence for selective Naᵥ1.7 inhibitors and most other interventions was of very low certainty. Treatment-response patterns in better-characterised populations suggest that aetiology and underlying mechanisms may be relevant to treatment selection. However, this mechanism-informed approach remains hypothesis-generating and requires prospective validation through systematic aetiological and mechanistic characterisation. This systematic review provides a comprehensive, graded evaluation of the full spectrum of pain-management strategies in erythromelalgia, including systemic, topical, interventional and non-pharmacological approaches, across reported aetiological subtypes. Integrating risk-of-bias appraisal and GRADE certainty ratings, it identifies moderate-certainty evidence for aspirin in myeloproliferative neoplasm-associated disease and low-certainty evidence for conventional sodium-channel blockers in selected primary forms, while evidence for other interventions remains low or very low. These patterns suggest that aetiology may inform treatment selection, but require prospective validation.
2026-08-17 | Sympathetic blocks in the treatment of erythromelalgia: case series.
Erythromelalgia (EM) is a rare, debilitating condition characterized by episodic burning pain, erythema, and increased skin temperature, typically affecting the distal extremities. EM significantly impairs quality of life (QoL) and may lead to functional disability. Although its pathophysiology is not fully understood, proposed mechanisms include small fiber nerve dysfunction and dysregulation of the sympathetic nervous system. Management remains challenging, with no universally effective treatment currently available. We present three patients with refractory lower extremity erythromelalgia treated with lumbar sympathetic block (LSB). All patients had chronic treatment-refractory symptoms and had failed multiple prior treatments, including neuropathic medications and conservative measures. Bilateral L3 LSBs were performed using a standardized approach. Two patients experienced substantial symptom improvement, with reported reductions in pain intensity and a prolonged benefit lasting several months. One patient demonstrated partial, short-term improvement. Repeated LSB procedures were performed in cases of symptom recurrence. In this retrospective case series, LSB was associated with symptomatic improvement in selected erythromelalgia patients, potentially by modulating sympathetic activity and regional blood flow. However, given the small sample size and retrospective design, no conclusions regarding efficacy can be drawn. Further studies are needed to better define patient selection criteria and long-term outcomes.
2026-06-26 | Invasive Spinal Neuromodulation for Chronic Pain in Pediatric Patients: A Scoping Review.
Chronic pain affects up to 21% of pediatric patients and significantly impairs function and quality of life. Although spinal neuromodulation, including spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S), has demonstrated efficacy in adults, evidence in children remains limited. This scoping review aims to systematically evaluate current evidence on spinal neuromodulation for pediatric chronic pain patients, focusing on clinical indications, outcomes, and safety. A structured scoping review was conducted using PubMed/MEDLINE and Scopus databases on June 8, 2025. Studies were included if they reported on patients under 21 years undergoing SCS or DRG-S for chronic pain. Two independent reviewers screened articles and extracted data on demographics, diagnoses, interventions, outcomes, and follow-up. Out of 706 references, 17 studies met inclusion criteria. Of those, 16 reported on SCS and 1 reported on DRG-S. complex regional pain syndrome (CRPS) was the most common indication, with most patients reporting substantial pain reduction, improved functional outcomes, and decreased medication use. Erythromelalgia was another frequent diagnosis treated successfully with SCS, demonstrating significant reductions in pain, swelling, and erythema. Other conditions included recurrent tethered cord syndrome, neurogenic thoracic outlet syndrome, lymphangioma, postoperative neuropathic pain, and genetic syndromes. Overall, most patients experienced meaningful improvements in pain and daily functioning, with few major complications reported. Spinal neuromodulation, predominantly SCS, appears to be a promising adjunctive therapy for refractory chronic pain in pediatric patients, particularly for CRPS and erythromelalgia. Despite encouraging findings, the evidence remains limited to small series and case reports. High-quality prospective studies are needed to establish long-term safety, efficacy, and optimal patient selection in this vulnerable population.
2026-06-25 | Co-Occurrence of SCN9A and PRRT2 Variants in a Patient With Paroxysmal Extreme Pain Disorder, Contradictory Analgesia, and Intractable Paroxysmal Non-Kinesigenic Dyskinesia.
Gain-of-function mutations in SCN9A, encoding the voltage-dependent Nav1.7 sodium channel, cause three autosomal-dominant disorders associated with severe pain: primary erythromelalgia, paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy. On the other hand, biallelic loss-of-function mutations have been linked to impaired pain perception. Notably, the coexistence of both hyperalgesia and hypoalgesia within the same patient harboring the I234T variant has been reported in three independent patients to date. We report a 7-year-old girl harboring co-occurring SCN9A (I234T) and PRRT2 variants who presented with paroxysmal extreme pain disorder, contradictory analgesia, sensitivity to heat, and intractable head-drop attacks. Based on the genetic and clinical analyses, she was diagnosed as having PEPD and PRRT2-related paroxysmal dyskinesia. The intractable head-drop attacks were considered as paroxysmal non-kinesigenic dyskinesia. In addition, she exhibited easy fatigability and hypotonia. Taken together with her cold, cyanotic feet, these findings suggest that she may have also had small fiber neuropathy.
gene therapies
2025-04-25 | Correction of sodium channel mutations in sensory neurons reverses aberrant properties.
Inherited erythromelalgia, small fibre neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. It remains unknown how different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations. Most of the work analysing the impact of these mutations on electrophysiological properties has used overexpression systems in cell lines and rodent sensory neurons, which might differ from the natural context. We have differentiated sensory neurons from induced pluripotent stem cells derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties, not previously observed in cell lines, that might be important for disease presentation. Furthermore, using CRISPR/Cas9, we corrected this mutation, which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders, and we introduced the mutation into control induced pluripotent stem cells, which generated hyperexcitability, providing causality. Induced pluripotent stem cell sensory neurons are a robust, scalable and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.
2025-03-14 | 1082 AAV-Based Upregulation of Potassium Channels as a Focal Treatment of Chronic Pain
INTRODUCTION: Efforts to treat pain by reducing the excitability of nociceptors (first order pain-sensing neurons), have focused on the NaV1.7 sodium channel, since loss of SCN9A (gene for NaV1.7) leads to congenital insensitivity to pain, whereas NaV1.7 gain-of-function mutation causes the severe painful syndrome familial erythromelalgia. Despite these genetic mutations and their distinct phenotypes, pharmacologic Nav!.7 targeting has not been a successful strategy. Most pain conditions are focal, yet most treatments are systemic and expose patients to potentially unnecessary systemic adverse side effects. METHODS: The effect of nociceptor specific potassium channel expression was confirmed by dissociated dorsal root ganglion (DRG) calcium imaging, and several rodent pain assays: von Frey mechanical threshold (sciatic injection), Hargreaves thermal threshold (sciatic injection), CFA inflammatory paw model (sciatic injection), and trigeminal neuralgia whisker pad mechanical threshold (trigeminal ganglion injection). Animals were either wild-type mice or TrpV1::ChR2-EYFP (expression of Channelorhodopsin-2 in TrpV1 lineage neurons). Treated animals were compared to age-, and sex-matched controls that received GFP-control virus in the same dose RESULTS: Animals treated with therapeutic potassium channels showed increased mechanical and thermal thresholds, decreased inflammatory response (higher mechanical threshold after CFA injection), and increased whisker pad thresholds compared to animals treated with GFP-control viruses. Animals that showed improved behavioral outcomes with potassium channel treatment were sacrificed and the DRGs dissociated. Calcium influx was lower in treated neurons when compared to GFP-controls supporting the hypothesis that hyperpolarization of nociceptors is a viable analgesic strategy. CONCLUSIONS: Our results validate the over-expression of potassium channels as a promising alternative for pain treatment and support the use of spatial restriction to achieve precision in AAV-mediated gene therapies.
2023-11-01 | Structural basis for severe pain caused by mutations in the voltage sensors of sodium channel NaV1.7.
Voltage-gated sodium channels in peripheral nerves conduct nociceptive signals from nerve endings to the spinal cord. Mutations in voltage-gated sodium channel NaV1.7 are responsible for a number of severe inherited pain syndromes, including inherited erythromelalgia (IEM). Here, we describe the negative shifts in the voltage dependence of activation in the bacterial sodium channel NaVAb as a result of the incorporation of four different IEM mutations in the voltage sensor, which recapitulate the gain-of-function effects observed with these mutations in human NaV1.7. Crystal structures of NaVAb with these IEM mutations revealed that a mutation in the S1 segment of the voltage sensor facilitated the outward movement of S4 gating charges by widening the pathway for gating charge translocation. In contrast, mutations in the S4 segments modified hydrophobic interactions with surrounding amino acid side chains or membrane phospholipids that would enhance the outward movement of the gating charges. These results provide key structural insights into the mechanisms by which these IEM mutations in the voltage sensors can facilitate outward movements of the gating charges in the S4 segment and cause hyperexcitability and severe pain in IEM. Our work gives new insights into IEM pathogenesis at the near-atomic level and provides a molecular model for mutation-specific therapy of this debilitating disease.
2013-03-28 | Molecular Architecture of a Sodium Channel S6 Helix
Voltage-gated sodium (NaV) channels are membrane proteins that consist of 24 transmembrane segments organized into four homologous domains and are essential for action potential generation and propagation. Although the S6 helices of NaV channels line the ion-conducting pore and participate in channel activation, their functional architecture is incompletely understood. Our recent studies show that a naturally occurring in-frame deletion mutation (Del-L955) of NaV1.7 channel, identified in individuals with a severe inherited pain syndrome (inherited erythromelalgia) causes a substantial hyperpolarizing shift of channel activation. Here we took advantage of this deletion mutation to understand the role of the S6 helix in the channel activation. Based on the recently published structure of a bacterial NaV channel (NaVAb), we modeled the WT and Del-L955 channel. Our structural model showed that Del-L955 twists the DII/S6 helix, shifting location and radial orientation of the activation gate residue (Phe960). Hypothesizing that these structural changes produce the shift of channel activation of Del-L955 channels, we restored a phenylalanine in wild-type orientation by mutating Ser961 (Del-L955/S961F), correcting activation by ∼10 mV. Correction of the displaced Phe960 (F960S) together with introduction of the rescuing activation gate residue (S961F) produced an additional ∼6-mV restoration of activation of the mutant channel. A simple point mutation in the absence of a twist (L955A) did not produce a radial shift and did not hyperpolarize activation. Our results demonstrate the functional importance of radial tuning of the sodium channel S6 helix for the channel activation.
2004-08-16 | Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.
Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na v 1.7, Na v 1.8, and Na v 1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na v 1.7 (PN1) in pain pathways. A global Na v 1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na v 1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na v 1.8 locus to generate heterozygous mice expressing Cre recombinase in Na v 1.8-positive sensory neurons. Crossing these animals with mice where Na v 1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na v 1.7 gene, SCN9A . Dominant Na v 1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na v 1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.
antibodies
2025-03-07 | Intravenous immunoglobulin therapy in erythromelalgia management: a case report.
A 49-year-old woman presented with a 16-year history of burning pain, warmth, redness, and edema in both toes, feet, legs and calves. Despite extensive medical testing, including genetic analysis, no specific cause was identified. Initial treatments failed to improve symptoms, leading to impaired quality of life and mental health. Eventually, a six-month course of intravenous immunoglobulin therapy provided complete relief, allowing the patient to resume normal activities. Erythromelalgia is a rare neurovascular condition characterized by pain, warmth, and erythema in the extremities. It can manifest as primary, inherited or sporadic, or secondary to underlying conditions, such as hematological neoplasms. Although genetic studies suggest a pivotal role of a gain-of-function mutation in the Nav1.7 voltage-gated sodium channel in familial cases, the pathogenesis underlying sporadic adult-onset cases remains uncertain. The frequent coexistence of autoimmune connective tissue diseases and the expanding evidence supporting immunotherapies in idiopathic small-fiber neuropathies underscores the possible involvement of adaptive immunity in such conditions. Given the potential complications in untreated patients, risks associated with long-term opioid therapy, and the absence of disease-modifying strategies, intravenous immunoglobulins may offer a more effective approach to pain control than conventional pain relievers, representing a promising direction for understanding the pathogenesis of erythromelalgia.
2024-02-10 | Erythromelalgia Secondary to Anti-Tumor Necrosis Factor (TNF) Alpha Therapy: A Report of Two Cases
Erythromelalgia is a rare syndrome with a generally unknown etiology. Whether primary or secondary, this condition is characterized by paroxysmal episodes of erythema, pain, and heat in the extremities. We report two cases of erythromelalgia occurring after the initiation of treatment with infliximab. The first case involves a 38-year-old patient who had been followed since August 2022 for ileocolonic Crohn's disease classified as A2L3B3 according to the Montreal classification, which was resistant to treatment and required infliximab therapy. Two months after the first infusion of infliximab, the patient developed symptoms of erythromelalgia. After ruling out other potential causes through an etiological assessment and conducting a pharmacological investigation, infliximab was considered the most likely cause. Infliximab was discontinued, and symptomatic treatment was initiated, including vascular laser sessions. The patient showed significant clinical improvement. In the second case, a 16-year-old patient with ileocolonic Crohn's disease classified as A1L3B3 according to the Montreal classification was treated with ileocecal resection and received an infusion of infliximab. Sixteen days after the second infusion, she developed clinical symptoms of erythromelalgia. The etiological assessment was inconclusive. Due to a strong suspicion of erythromelalgia secondary to tumor necrosis factor (TNF) alpha inhibitor therapy, infliximab was replaced with ustekinumab. The patient also received symptomatic treatment, and her clinical condition improved, marked by the disappearance of pain.
2023-11-29 | A case of erythromelalgia with gastrointestinal dysautonomia treated with immunoglobulin: A case report.
An 18-year-old female with a history of atopic march, hyperhidrosis, and eosinophilic esophagitis was diagnosed with erythromelalgia and gastrointestinal dysautonomia secondary to presumed autoimmune small fiber neuropathy. The patient experienced significant clinical improvements after the initiation of intravenous immunoglobulin therapy, supporting an underlying autoimmune disorder.
2019-03-15 | Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics.
Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel NaV1.7, is being pursued to address the unmet medical need with respect to chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed NaV1.7 inhibitory peptide-antibody conjugates with tarantula venom-derived GpTx-1 toxin peptides with an extended half-life (80 h) in rodents but only moderate in vitro activity (hNaV1.7 IC50 = 250 nM) and without in vivo activity. We identified the more potent peptide JzTx-V from our natural peptide collection and improved its selectivity against other sodium channel isoforms through positional analogueing. Here we report utilization of the JzTx-V scaffold in a peptide-antibody conjugate and architectural variations in the linker, peptide loading, and antibody attachment site. We found conjugates with 100-fold improved in vitro potency relative to those of complementary GpTx-1 analogues, but pharmacokinetic and bioimaging analyses of these JzTx-V conjugates revealed a shorter than expected plasma half-life in vivo with accumulation in the liver. In an attempt to increase circulatory serum levels, we sought the reduction of the net +6 charge of the JzTx-V scaffold while retaining a desirable NaV in vitro activity profile. The conjugate of a JzTx-V peptide analogue with a +2 formal charge maintained NaV1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss of peptide and conjugate potency associated with the reduction of net charge necessary for improved target exposure resulted in a compound with moderate activity in a NaV1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage NaV1.7 in vivo.
2018-01-14 | Differential Inhibition of Nav1.7 and Neuropathic Pain by Hybridoma-Produced and Recombinant Monoclonal Antibodies that Target Nav1.7
The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
proteins
2023-12-21 | Elucidating molecular mechanisms of protoxin-II state-specific binding to the human NaV1.7 channel
Human voltage-gated sodium (hNaV) channels are responsible for initiating and propagating action potentials in excitable cells, and mutations have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels are expressed in peripheral neurons and are promising targets for pain therapy. The tarantula venom peptide protoxin-II (PTx2) has high selectivity for hNaV1.7 and is a valuable scaffold for designing novel therapeutics to treat pain. Here, we used computational modeling to study the molecular mechanisms of the state-dependent binding of PTx2 to hNaV1.7 voltage-sensing domains (VSDs). Using Rosetta structural modeling methods, we constructed atomistic models of the hNaV1.7 VSD II and IV in the activated and deactivated states with docked PTx2. We then performed microsecond-long all-atom molecular dynamics (MD) simulations of the systems in hydrated lipid bilayers. Our simulations revealed that PTx2 binds most favorably to the deactivated VSD II and activated VSD IV. These state-specific interactions are mediated primarily by PTx2’s residues R22, K26, K27, K28, and W30 with VSD and the surrounding membrane lipids. Our work revealed important protein–protein and protein–lipid contacts that contribute to high-affinity state-dependent toxin interaction with the channel. The workflow presented will prove useful for designing novel peptides with improved selectivity and potency for more effective and safe treatment of pain.
2023-10-06 | A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.
Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM4-GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically approved drug varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioral hyposensitivity upon agonist administration, which was recovered upon agonist washout. Stable expression of the channel led to similar reversible suppression of pain-related behavior even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM4-GlyR activation in acute and joint pain inflammation mouse models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioral hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM4-GlyR activation decreased the excitability of human-induced pluripotent stem cell-derived sensory neurons and spontaneous activity due to a gain-of-function NaV1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable, and reversible humanized chemogenetic system for the treatment of pain.
2023-03-21 | Inhibition of sensory neuron driven acute, inflammatory, and neuropathic pain using a humanised chemogenetic system
Abstract Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM 4 -GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically-approved drug, varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally-mediated expression of PSAM 4 -GlyR in mouse sensory neurons produced behavioural hyposensitivity upon agonist administration, which was recovered upon agonist washout. Importantly, stable expression of the channel led to similar reversible behavioural effects even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM 4 -GlyR activation in acute and joint pain inflammation models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioural hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM 4 -GlyR activation decreased the excitability of human induced pluripotent stem-cell-derived sensory neurons and spontaneous activity due to a gain of function Na V 1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable and reversible human-based chemogenetic system for the treatment of pain.
2021-06-21 | Uncoupling sodium channel dimers restores the phenotype of a pain-linked Nav 1.7 channel mutation.
The voltage-gated sodium channel Nav 1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans. The hNav 1.7/A1632E channel mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage-gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is altered by the hNav 1.7/A1632E mutation, and how dimerization modifies function of the pain-linked mutation. We applied atomistic molecular simulations to demonstrate the effect of the mutation on channel fast inactivation. Native PAGE was used to demonstrate channel dimerization, and electrophysiological measurements in HEK cells and Xenopus laevis oocytes were used to analyze the links between functional channel dimerization and impairment of fast inactivation by the hNav 1.7/A1632E mutation. Enhanced persistent current through hNav 1.7/A1632E channels was caused by impaired binding of the inactivation particle, which inhibits proper functioning of the recently proposed allosteric fast inactivation mechanism. hNav 1.7 channels form dimers and the disease-associated persistent current through hNav 1.7/A1632E channels depends on their functional dimerization status: Expression of the synthetic peptide difopein, a 14-3-3 inhibitor known to functionally uncouple dimers, decreased hNav 1.7/A1632E channel-induced persistent currents. Functional uncoupling of mutant hNav 1.7/A1632E channel dimers restored their defective allosteric fast inactivation mechanism. Our findings support the concept of sodium channel dimerization and reveal its potential relevance for human pain syndromes.
2021-01-28 | Spider Venom Peptide Pn3a Inhibition of Primary Afferent High Voltage-Activated Calcium Channels
Despite potently inhibiting the nociceptive voltage-gated sodium (Na v ) channel, Na v 1.7, µ -theraphotoxin Pn3a is antinociceptive only upon co-administration with sub-therapeutic opioid agonists, or by itself at doses >3,000-fold greater than its Na v 1.7 IC 50 by a yet undefined mechanism. Na v channels are structurally related to voltage-gated calcium (Ca v ) channels, Ca v 1 and Ca v 2. These channels mediate the high voltage-activated (HVA) calcium currents ( I Ca ) that orchestrate synaptic transmission in nociceptive dorsal root ganglion (DRG) neurons and are fine-tuned by opioid receptor (OR) activity. Using whole-cell patch clamp recording, we found that Pn3a (10 µM) inhibits ∼55% of rat DRG neuron HVA- I Ca and 60–80% of Ca v 1.2, Ca v 1.3, Ca v 2.1, and Ca v 2.2 mediated currents in HEK293 cells, with no inhibition of Ca v 2.3. As a major DRG I Ca component, Ca v 2.2 inhibition by Pn3a ( IC 50 = 3.71 ± 0.21 µM) arises from an 18 mV hyperpolarizing shift in the voltage dependence of inactivation. We observed that co-application of Pn3a and µ-OR agonist DAMGO results in enhanced HVA- I Ca inhibition in DRG neurons whereas co-application of Pn3a with the OR antagonist naloxone does not, underscoring HVA channels as shared targets of Pn3a and opioids. We provide evidence that Pn3a inhibits native and recombinant HVA Ca v s at previously reportedly antinociceptive concentrations in animal pain models. We show additive modulation of DRG HVA- I Ca by sequential application of low Pn3a doses and sub-therapeutic opioids ligands. We propose Pn3a's antinociceptive effects result, at least in part, from direct inhibition of HVA- I Ca at high Pn3a doses, or through additive inhibition by low Pn3a and mild OR activation.
small molecules
2026-09-08 | A Case of Refractory Erythromelalgia Treated Successfully with Suzetrigine, a Selective Sodium Channel Blocker
Background: Erythromelalgia is an uncommon neurovascular pain disorder characterized by episodic erythema, warmth, and burning pain, typically affecting the distal extremities. This condition can be debilitating and difficult to treat, often resulting in poor response to multiple therapies. Hereditary forms are often linked to mutations in the SCN9A gene, which encodes the NaV1.7 sodium channel, resulting in hyperexcitability of nociceptive neurons. Case Presentation: A 31-year-old male presented with a lifelong history of recurrent redness, warmth, and pain involving the bilateral hands and feet. Clinical diagnosis was based on characteristic symptoms and family history, notable for similar findings in his mother and children, suggesting a hereditary component. Multiple standard therapies provided minimal relief, including low-dose and high-dose aspirin, amitriptyline, doxepin, pregabalin, gabapentin, venlafaxine, colchicine, and compounded topical formulations containing amitriptyline, ketamine, and lidocaine. He was started on the non-opioid analgesic suzetrigine (Journavx) 50 mg daily, a novel selective NaV1.8 sodium channel blocker, by a pain specialist for off-label management of chronic low back pain. Within one month, he reported greater than 75% improvement in pain, erythema, and flare duration, along with significant improvement in quality of life. Discussion & Conclusion: This case highlights the potential of targeted sodium channel blockade in erythromelalgia. Although suzetrigine selectively inhibits NaV1.8, its downstream interaction with NaV1.7 in pain signal propagation suggests possible mechanistic overlap. In this patient with refractory erythromelalgia, treatment with suzetrigine was associated with meaningful improvement. Further studies are necessary to better characterize the efficacy and broader applicability of this alternative therapeutic approach.
2026-09-04 | Pain Management in Erythromelalgia: A Systematic Review and Graded Appraisal Across Etiological Subtypes.
Erythromelalgia is a rare disorder characterised by burning pain, erythema and increased skin temperature in the extremities. Its pathophysiological heterogeneity, together with variable treatment responses, complicates management in the absence of evidence-based guidelines. This systematic review appraised pain-management strategies across reported aetiological subtypes. Following PRISMA 2020 guidelines, the review was registered in PROSPERO (CRD420251232074). PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched for studies published or registered between 1 January 2000 and 30 April 2026. Randomised controlled trials, non-randomised interventional studies, cohort studies and case series were eligible; non-randomised studies required at least five individuals. Risk of bias was assessed using Joanna Briggs Institute tools and certainty of evidence using GRADE. Of 3372 records, 25 studies reporting 591 individuals were included. Aetiological subtype was reported for 277 individuals (46.9%). Mechanistic and aetiological characterisation varied substantially across domains, with haematological data available for 72.6% and SCN9A status for 19.0% of the overall population. Moderate-certainty evidence supported aspirin in myeloproliferative neoplasm-associated erythromelalgia. Low-certainty evidence suggested benefit from mexiletine and carbamazepine in primary erythromelalgia, as well as from prostaglandin analogues, corticosteroids, selected topical therapies and sympathetic interventions in specific contexts. Evidence for selective Naᵥ1.7 inhibitors and most other interventions was of very low certainty. Treatment-response patterns in better-characterised populations suggest that aetiology and underlying mechanisms may be relevant to treatment selection. However, this mechanism-informed approach remains hypothesis-generating and requires prospective validation through systematic aetiological and mechanistic characterisation. This systematic review provides a comprehensive, graded evaluation of the full spectrum of pain-management strategies in erythromelalgia, including systemic, topical, interventional and non-pharmacological approaches, across reported aetiological subtypes. Integrating risk-of-bias appraisal and GRADE certainty ratings, it identifies moderate-certainty evidence for aspirin in myeloproliferative neoplasm-associated disease and low-certainty evidence for conventional sodium-channel blockers in selected primary forms, while evidence for other interventions remains low or very low. These patterns suggest that aetiology may inform treatment selection, but require prospective validation.
2026-08-17 | Sympathetic blocks in the treatment of erythromelalgia: case series.
Erythromelalgia (EM) is a rare, debilitating condition characterized by episodic burning pain, erythema, and increased skin temperature, typically affecting the distal extremities. EM significantly impairs quality of life (QoL) and may lead to functional disability. Although its pathophysiology is not fully understood, proposed mechanisms include small fiber nerve dysfunction and dysregulation of the sympathetic nervous system. Management remains challenging, with no universally effective treatment currently available. We present three patients with refractory lower extremity erythromelalgia treated with lumbar sympathetic block (LSB). All patients had chronic treatment-refractory symptoms and had failed multiple prior treatments, including neuropathic medications and conservative measures. Bilateral L3 LSBs were performed using a standardized approach. Two patients experienced substantial symptom improvement, with reported reductions in pain intensity and a prolonged benefit lasting several months. One patient demonstrated partial, short-term improvement. Repeated LSB procedures were performed in cases of symptom recurrence. In this retrospective case series, LSB was associated with symptomatic improvement in selected erythromelalgia patients, potentially by modulating sympathetic activity and regional blood flow. However, given the small sample size and retrospective design, no conclusions regarding efficacy can be drawn. Further studies are needed to better define patient selection criteria and long-term outcomes.
2026-06-26 | Invasive Spinal Neuromodulation for Chronic Pain in Pediatric Patients: A Scoping Review.
Chronic pain affects up to 21% of pediatric patients and significantly impairs function and quality of life. Although spinal neuromodulation, including spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S), has demonstrated efficacy in adults, evidence in children remains limited. This scoping review aims to systematically evaluate current evidence on spinal neuromodulation for pediatric chronic pain patients, focusing on clinical indications, outcomes, and safety. A structured scoping review was conducted using PubMed/MEDLINE and Scopus databases on June 8, 2025. Studies were included if they reported on patients under 21 years undergoing SCS or DRG-S for chronic pain. Two independent reviewers screened articles and extracted data on demographics, diagnoses, interventions, outcomes, and follow-up. Out of 706 references, 17 studies met inclusion criteria. Of those, 16 reported on SCS and 1 reported on DRG-S. complex regional pain syndrome (CRPS) was the most common indication, with most patients reporting substantial pain reduction, improved functional outcomes, and decreased medication use. Erythromelalgia was another frequent diagnosis treated successfully with SCS, demonstrating significant reductions in pain, swelling, and erythema. Other conditions included recurrent tethered cord syndrome, neurogenic thoracic outlet syndrome, lymphangioma, postoperative neuropathic pain, and genetic syndromes. Overall, most patients experienced meaningful improvements in pain and daily functioning, with few major complications reported. Spinal neuromodulation, predominantly SCS, appears to be a promising adjunctive therapy for refractory chronic pain in pediatric patients, particularly for CRPS and erythromelalgia. Despite encouraging findings, the evidence remains limited to small series and case reports. High-quality prospective studies are needed to establish long-term safety, efficacy, and optimal patient selection in this vulnerable population.
2026-06-25 | Co-Occurrence of SCN9A and PRRT2 Variants in a Patient With Paroxysmal Extreme Pain Disorder, Contradictory Analgesia, and Intractable Paroxysmal Non-Kinesigenic Dyskinesia.
Gain-of-function mutations in SCN9A, encoding the voltage-dependent Nav1.7 sodium channel, cause three autosomal-dominant disorders associated with severe pain: primary erythromelalgia, paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy. On the other hand, biallelic loss-of-function mutations have been linked to impaired pain perception. Notably, the coexistence of both hyperalgesia and hypoalgesia within the same patient harboring the I234T variant has been reported in three independent patients to date. We report a 7-year-old girl harboring co-occurring SCN9A (I234T) and PRRT2 variants who presented with paroxysmal extreme pain disorder, contradictory analgesia, sensitivity to heat, and intractable head-drop attacks. Based on the genetic and clinical analyses, she was diagnosed as having PEPD and PRRT2-related paroxysmal dyskinesia. The intractable head-drop attacks were considered as paroxysmal non-kinesigenic dyskinesia. In addition, she exhibited easy fatigability and hypotonia. Taken together with her cold, cyanotic feet, these findings suggest that she may have also had small fiber neuropathy.
gene therapies
2025-04-25 | Correction of sodium channel mutations in sensory neurons reverses aberrant properties.
Inherited erythromelalgia, small fibre neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. It remains unknown how different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations. Most of the work analysing the impact of these mutations on electrophysiological properties has used overexpression systems in cell lines and rodent sensory neurons, which might differ from the natural context. We have differentiated sensory neurons from induced pluripotent stem cells derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties, not previously observed in cell lines, that might be important for disease presentation. Furthermore, using CRISPR/Cas9, we corrected this mutation, which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders, and we introduced the mutation into control induced pluripotent stem cells, which generated hyperexcitability, providing causality. Induced pluripotent stem cell sensory neurons are a robust, scalable and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.
2025-03-14 | 1082 AAV-Based Upregulation of Potassium Channels as a Focal Treatment of Chronic Pain
INTRODUCTION: Efforts to treat pain by reducing the excitability of nociceptors (first order pain-sensing neurons), have focused on the NaV1.7 sodium channel, since loss of SCN9A (gene for NaV1.7) leads to congenital insensitivity to pain, whereas NaV1.7 gain-of-function mutation causes the severe painful syndrome familial erythromelalgia. Despite these genetic mutations and their distinct phenotypes, pharmacologic Nav!.7 targeting has not been a successful strategy. Most pain conditions are focal, yet most treatments are systemic and expose patients to potentially unnecessary systemic adverse side effects. METHODS: The effect of nociceptor specific potassium channel expression was confirmed by dissociated dorsal root ganglion (DRG) calcium imaging, and several rodent pain assays: von Frey mechanical threshold (sciatic injection), Hargreaves thermal threshold (sciatic injection), CFA inflammatory paw model (sciatic injection), and trigeminal neuralgia whisker pad mechanical threshold (trigeminal ganglion injection). Animals were either wild-type mice or TrpV1::ChR2-EYFP (expression of Channelorhodopsin-2 in TrpV1 lineage neurons). Treated animals were compared to age-, and sex-matched controls that received GFP-control virus in the same dose RESULTS: Animals treated with therapeutic potassium channels showed increased mechanical and thermal thresholds, decreased inflammatory response (higher mechanical threshold after CFA injection), and increased whisker pad thresholds compared to animals treated with GFP-control viruses. Animals that showed improved behavioral outcomes with potassium channel treatment were sacrificed and the DRGs dissociated. Calcium influx was lower in treated neurons when compared to GFP-controls supporting the hypothesis that hyperpolarization of nociceptors is a viable analgesic strategy. CONCLUSIONS: Our results validate the over-expression of potassium channels as a promising alternative for pain treatment and support the use of spatial restriction to achieve precision in AAV-mediated gene therapies.
2023-11-01 | Structural basis for severe pain caused by mutations in the voltage sensors of sodium channel NaV1.7.
Voltage-gated sodium channels in peripheral nerves conduct nociceptive signals from nerve endings to the spinal cord. Mutations in voltage-gated sodium channel NaV1.7 are responsible for a number of severe inherited pain syndromes, including inherited erythromelalgia (IEM). Here, we describe the negative shifts in the voltage dependence of activation in the bacterial sodium channel NaVAb as a result of the incorporation of four different IEM mutations in the voltage sensor, which recapitulate the gain-of-function effects observed with these mutations in human NaV1.7. Crystal structures of NaVAb with these IEM mutations revealed that a mutation in the S1 segment of the voltage sensor facilitated the outward movement of S4 gating charges by widening the pathway for gating charge translocation. In contrast, mutations in the S4 segments modified hydrophobic interactions with surrounding amino acid side chains or membrane phospholipids that would enhance the outward movement of the gating charges. These results provide key structural insights into the mechanisms by which these IEM mutations in the voltage sensors can facilitate outward movements of the gating charges in the S4 segment and cause hyperexcitability and severe pain in IEM. Our work gives new insights into IEM pathogenesis at the near-atomic level and provides a molecular model for mutation-specific therapy of this debilitating disease.
2013-03-28 | Molecular Architecture of a Sodium Channel S6 Helix
Voltage-gated sodium (NaV) channels are membrane proteins that consist of 24 transmembrane segments organized into four homologous domains and are essential for action potential generation and propagation. Although the S6 helices of NaV channels line the ion-conducting pore and participate in channel activation, their functional architecture is incompletely understood. Our recent studies show that a naturally occurring in-frame deletion mutation (Del-L955) of NaV1.7 channel, identified in individuals with a severe inherited pain syndrome (inherited erythromelalgia) causes a substantial hyperpolarizing shift of channel activation. Here we took advantage of this deletion mutation to understand the role of the S6 helix in the channel activation. Based on the recently published structure of a bacterial NaV channel (NaVAb), we modeled the WT and Del-L955 channel. Our structural model showed that Del-L955 twists the DII/S6 helix, shifting location and radial orientation of the activation gate residue (Phe960). Hypothesizing that these structural changes produce the shift of channel activation of Del-L955 channels, we restored a phenylalanine in wild-type orientation by mutating Ser961 (Del-L955/S961F), correcting activation by ∼10 mV. Correction of the displaced Phe960 (F960S) together with introduction of the rescuing activation gate residue (S961F) produced an additional ∼6-mV restoration of activation of the mutant channel. A simple point mutation in the absence of a twist (L955A) did not produce a radial shift and did not hyperpolarize activation. Our results demonstrate the functional importance of radial tuning of the sodium channel S6 helix for the channel activation.
2004-08-16 | Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.
Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na v 1.7, Na v 1.8, and Na v 1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na v 1.7 (PN1) in pain pathways. A global Na v 1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na v 1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na v 1.8 locus to generate heterozygous mice expressing Cre recombinase in Na v 1.8-positive sensory neurons. Crossing these animals with mice where Na v 1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na v 1.7 gene, SCN9A . Dominant Na v 1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na v 1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.
antibodies
2025-03-07 | Intravenous immunoglobulin therapy in erythromelalgia management: a case report.
A 49-year-old woman presented with a 16-year history of burning pain, warmth, redness, and edema in both toes, feet, legs and calves. Despite extensive medical testing, including genetic analysis, no specific cause was identified. Initial treatments failed to improve symptoms, leading to impaired quality of life and mental health. Eventually, a six-month course of intravenous immunoglobulin therapy provided complete relief, allowing the patient to resume normal activities. Erythromelalgia is a rare neurovascular condition characterized by pain, warmth, and erythema in the extremities. It can manifest as primary, inherited or sporadic, or secondary to underlying conditions, such as hematological neoplasms. Although genetic studies suggest a pivotal role of a gain-of-function mutation in the Nav1.7 voltage-gated sodium channel in familial cases, the pathogenesis underlying sporadic adult-onset cases remains uncertain. The frequent coexistence of autoimmune connective tissue diseases and the expanding evidence supporting immunotherapies in idiopathic small-fiber neuropathies underscores the possible involvement of adaptive immunity in such conditions. Given the potential complications in untreated patients, risks associated with long-term opioid therapy, and the absence of disease-modifying strategies, intravenous immunoglobulins may offer a more effective approach to pain control than conventional pain relievers, representing a promising direction for understanding the pathogenesis of erythromelalgia.
2024-02-10 | Erythromelalgia Secondary to Anti-Tumor Necrosis Factor (TNF) Alpha Therapy: A Report of Two Cases
Erythromelalgia is a rare syndrome with a generally unknown etiology. Whether primary or secondary, this condition is characterized by paroxysmal episodes of erythema, pain, and heat in the extremities. We report two cases of erythromelalgia occurring after the initiation of treatment with infliximab. The first case involves a 38-year-old patient who had been followed since August 2022 for ileocolonic Crohn's disease classified as A2L3B3 according to the Montreal classification, which was resistant to treatment and required infliximab therapy. Two months after the first infusion of infliximab, the patient developed symptoms of erythromelalgia. After ruling out other potential causes through an etiological assessment and conducting a pharmacological investigation, infliximab was considered the most likely cause. Infliximab was discontinued, and symptomatic treatment was initiated, including vascular laser sessions. The patient showed significant clinical improvement. In the second case, a 16-year-old patient with ileocolonic Crohn's disease classified as A1L3B3 according to the Montreal classification was treated with ileocecal resection and received an infusion of infliximab. Sixteen days after the second infusion, she developed clinical symptoms of erythromelalgia. The etiological assessment was inconclusive. Due to a strong suspicion of erythromelalgia secondary to tumor necrosis factor (TNF) alpha inhibitor therapy, infliximab was replaced with ustekinumab. The patient also received symptomatic treatment, and her clinical condition improved, marked by the disappearance of pain.
2023-11-29 | A case of erythromelalgia with gastrointestinal dysautonomia treated with immunoglobulin: A case report.
An 18-year-old female with a history of atopic march, hyperhidrosis, and eosinophilic esophagitis was diagnosed with erythromelalgia and gastrointestinal dysautonomia secondary to presumed autoimmune small fiber neuropathy. The patient experienced significant clinical improvements after the initiation of intravenous immunoglobulin therapy, supporting an underlying autoimmune disorder.
2019-03-15 | Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics.
Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel NaV1.7, is being pursued to address the unmet medical need with respect to chronic pain and the rising opioid epidemic. As part of early research efforts on this front, we have previously developed NaV1.7 inhibitory peptide-antibody conjugates with tarantula venom-derived GpTx-1 toxin peptides with an extended half-life (80 h) in rodents but only moderate in vitro activity (hNaV1.7 IC50 = 250 nM) and without in vivo activity. We identified the more potent peptide JzTx-V from our natural peptide collection and improved its selectivity against other sodium channel isoforms through positional analogueing. Here we report utilization of the JzTx-V scaffold in a peptide-antibody conjugate and architectural variations in the linker, peptide loading, and antibody attachment site. We found conjugates with 100-fold improved in vitro potency relative to those of complementary GpTx-1 analogues, but pharmacokinetic and bioimaging analyses of these JzTx-V conjugates revealed a shorter than expected plasma half-life in vivo with accumulation in the liver. In an attempt to increase circulatory serum levels, we sought the reduction of the net +6 charge of the JzTx-V scaffold while retaining a desirable NaV in vitro activity profile. The conjugate of a JzTx-V peptide analogue with a +2 formal charge maintained NaV1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss of peptide and conjugate potency associated with the reduction of net charge necessary for improved target exposure resulted in a compound with moderate activity in a NaV1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage NaV1.7 in vivo.
2018-01-14 | Differential Inhibition of Nav1.7 and Neuropathic Pain by Hybridoma-Produced and Recombinant Monoclonal Antibodies that Target Nav1.7
The voltage-gated Na+ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na+ currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na+ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na+ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
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Drug Discovery Landscape
9 orphan drug designations for Primary erythromelalgia.
9 orphan drug designations for Primary erythromelalgia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
N-[(1S)-1-(4-Tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide | small molecules | EMA | — | AlzeCure Pharma AB |
replication-defective herpes simplex virus type 1 (rdHSV-1) vector designed to deliver a variant of the transgene coding for the human carbonic anhydrase 8 (CA8-201) analgesic peptide with a V5 tag inserted at the C-terminal end (V5CA8) | gene therapies | FDA | — | Adolore BioTherapeutics, Inc. |
N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7- difluoro-1H-benzimidazol-1-yl)acetamide hydrogen sulphate salt | small molecules | FDA | — | AlzeCure Pharma AB |
Tetrahydronaphthyl urea based selective TRPV1 antagonist | small molecules | FDA | — | Pila Pharma AB |
Amitriptyline | small molecules | EMA | AlgoTherapeutix | |
Amitriptyline | small molecules | FDA | Algo Therapeutix S.A.S | |
vixotrigine | small molecules | FDA | Biogen, Inc. | |
1'-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one | small molecules | FDA | Flexion Therapeutics, Inc. | |
capsaicin | small molecules | FDA | — | Averitas Pharma, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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