Intranasal CRMP2-Ubc9 inhibitor regulates Na V 1.7 to alleviate trigeminal neuropathic pain.

ABSTRACT: Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of Na V 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we used a comprehensive array of approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve, 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating Na V 1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.

Protection against COVID-19 hospitalisation conferred by primary-series vaccination with AZD1222 in non-boosted individuals: first vaccine effectiveness results of the European COVIDRIVE study and meta-regression analysis.

Background: Vaccine effectiveness (VE) studies with long-term follow-up are needed to understand durability of protection against severe COVID-19 outcomes conferred by primary-series vaccination in individuals not receiving boosters. COVIDRIVE is a European public-private partnership evaluating brand-specific vaccine effectiveness (VE). We report a prespecified interim analysis of primary-series AZD1222 (ChAdOx1 nCoV-19) VE. Methods: Seven Study Contributors in Europe collected data on individuals aged ≥18 years who were hospitalised with severe acute respiratory infection (June 1st, 2021-September 5th, 2022) and eligible for COVID-19 vaccination prior to hospitalisation. In this test-negative case-control study, individuals were defined as test-positive cases or test-negative controls (SARS-CoV-2 RT-PCR) and were either fully vaccinated (two AZD1222 doses, 4-12 weeks apart, completed ≥14 days prior to symptom onset; no booster doses) or unvaccinated (no COVID-19 vaccine prior to hospitalisation). The primary objective was to estimate AZD1222 VE against COVID-19 hospitalisation. A literature review and meta-regression were conducted to contextualise findings on durability of protection. Findings: 761 individuals were included during the 15-month analysis period. Overall AZD1222 VE estimate was 72.8% (95% CI, 53.4-84.1). VE was 93.8% (48.6-99.3) in participants who received second AZD1222 doses ≤8 weeks prior to hospitalisation, with spline-based VE estimates demonstrating protection (VE ≥ 50%) 30 weeks post-second dose. Meta-regression analysis (data from seven publications) showed consistent results, with ≥80% protection against COVID-19 hospitalisation through ∼43 weeks post-second dose, with some degree of waning. Interpretation: Primary-series AZD1222 vaccination confers protection against COVID-19 hospitalisation with enduring levels of VE through ≥6 months. Funding: AstraZeneca.

Intranasal CRMP2-Ubc9 Inhibitor Regulates Na V 1.7 to Alleviate Trigeminal Neuropathic Pain.

Dysregulation of voltage-gated sodium Na V 1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/Na V 1.7 interaction and increased functional activity of Na V 1.7. Targeting this feed-forward regulation, we developed compound 194 , which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of Na V 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of Na V 1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and Na V 1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/Na V 1.7 interaction, impeded Na V 1.7 diffusion on the plasma membrane, and subsequently diminished Na V 1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating Na V 1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.