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Herpes Simplex Virus (HSV) is primarily categorized into HSV-1 and HSV-2. The former often causes oral herpes, while the latter is a major cause of genital herpes. Both viruses can disseminate to other organs or lead to severe, potentially fatal complications, including herpes keratitis, herpes encephalitis, neonatal herpes, among others. Existing therapeutics like acyclovir can only inhibit viral replication but cannot prevent latent infection or recurrence. Furthermore, as the viral glycoprotein B (gB) undergoes conformational changes, the number of drug-resistant viral strains continues to rise annually.

The lack of effective treatments for brain disorders related to NMDA receptor hypofunction, such as schizophrenia and GRIN1-related disorders, has long been a major challenge in the medical field. Traditional small-molecule drugs often lack selectivity and exhibit significant side effects, while antibody-based therapies struggle to cross the blood-brain barrier (BBB), limiting their efficacy.To address this clinical need, a collaborative effort involving the Institute of Functional Genomics in Montpellier (France), the Department of Pharmacology and Toxicology at the University of Toronto (Canada), and the Faculty of Health, Medicine, and Technology at Paris-Saclay University (France) has developed a bivalent bispecific nanobody named DN13-DN1. Administered via intraperitoneal (IP) injection, this nanobody successfully crosses the BBB, specifically binds to and enhances the activity of the mGlu2 receptor. In two mouse models of NMDA receptor hypofunction—neonatal PCP-induced (mimicking schizophrenia) and GluN1-KD genetic (mimicking GRIN1 disorder)—DN13-DN1 significantly improved cognitive deficits and sensorimotor gating impairments. Subchronic treatment demonstrated stable therapeutic effects without noticeable side effects, outperforming both traditional small-molecule drugs and IgG-class antibodies. This study was published in the leading academic journal Nature. Let’s delve into the details.

在精神分裂症、GRIN1障碍等NMDA受体功能低下相关脑疾病领域，高效治疗手段的匮乏一直是医学界的痛点。传统小分子药物选择性差、副作用明显，而抗体类药物又因血脑屏障穿透性差难以发挥作用。针对这一临床痛点，法国蒙彼利埃功能基因组研究所、加拿大多伦多大学药理学与毒理学系、法国巴黎萨克雷大学健康药物与技术系等多家机构联合开发了一种名为DN13-DN1的双价双特异性纳米抗体，在经过腹腔注射后可穿透血脑屏障，特异性结合并增强mGlu2受体活性，在新生期PCP诱导(模拟精神分裂症)和GluN1-KD遗传(模拟GRIN1障碍)两种NMDA受体功能低下小鼠模型中能显著改善认知缺陷与感觉运动门控障碍，亚慢性治疗效果稳定且无明显副作用，其效果优于传统小分子药物与IgG类抗体。该研究发表于全球顶尖学术期刊《Nature》，让我们一起来解读这项研究。