Risperidone

#关爱孤独症在行动# 引言 孤独症谱系障碍（ASD）是一类以社交沟通障碍、重复刻板行为为核心特征的神经发育性疾病，全球患病率接近1.5%。其病因涉及数百个风险基因与环境因素的复杂交互，目前仍缺乏有效的靶向治疗药物。从基因发现到药物候选物的转化，是ASD药物研发面临的核心挑战。 斑马鱼（Danio rerio）作为一种新兴模式生物，凭借其遗传保守性、胚胎透明及高通量筛选优势，正快速崛起为连接基础研究与药物开发的重要桥梁。本文系统梳理斑马鱼模型在ASD药物研发领域的应用进展，以期为相关研究提供参考。 一、斑马鱼模型的独特优势 1.1 遗传与生理的高度保守性 斑马鱼与人类的遗传相似性远超人们的直观认知。研究表明，斑马鱼约70%的蛋白编码基因与人类具有同源性，高达82%的人类疾病相关基因可在斑马鱼中找到对应同源基因。尤为重要的是，斑马鱼中枢神经系统在宏观组织、细胞形态、主要神经递质系统和功能性神经内分泌系统方面与人类高度相似。这种高度的遗传和生理保守性，为研究人类神经发育疾病机制提供了可靠模型。 1.2 高通量药物筛选的天然优势 斑马鱼模型的实验优势使其成为药物筛选的理想平台。雌性斑马鱼单次可产卵200-300枚，胚胎在体外受精、体外发育，发育早期完全透明。这些特性使研究人员能够实时观察药物对神经系统发育的影响，并可同时进行大规模药物筛选。 2026年，美国耶鲁大学研究团队在《美国国家科学院院刊》（PNAS）上发表了一项突破性研究，利用斑马鱼幼虫建立了包含520种美国FDA批准药物的行为特征数据库，并对9个ASD高风险基因突变体的行为表型进行分析，成功筛选出能够抑制突变体行为异常的候选药物。这一研究充分展示了斑马鱼在药物发现中的规模化优势。 二、孤独症斑马鱼模型的构建策略 2.1 基因编辑模型 随着CRISPR/Cas9基因编辑技术的成熟，研究者已构建了多种ASD相关基因的斑马鱼模型。这些模型涵盖了ASD的主要遗传风险因素： Katnal2突变模型：2026年发表于《The ISME Journal》的研究利用Katnal2突变斑马鱼作为ASD样模型，评估了粪菌移植和益生菌补充对神经发育缺陷的改善作用。这一模型为研究肠-脑轴在ASD中的作用提供了重要工具。 SCN2A与DYRK1A突变模型：耶鲁大学团队在PNAS发表的研究中，构建了SCN2A和DYRK1A基因突变斑马鱼，并通过高通量药物筛选发现了左卡尼汀（LEVO）等能够显著改善两种突变体行为表型的候选药物。重要的是，这些发现进一步在携带相同突变的人类干细胞分化神经元中得到验证，展示了跨物种的保守性。 slc6a3敲除模型：郑州大学第一附属医院团队利用CRISPR-Cas9技术构建了slc6a3基因敲除斑马鱼模型。该基因编码多巴胺转运蛋白（DAT），其功能障碍与ASD密切相关。研究发现，slc6a3敲除导致多巴胺水平显著降低，行为上表现出运动能力下降、焦虑样行为增加、社交能力受损和“挖掘”样刻板行为。这一模型为研究多巴胺系统功能紊乱与ASD的关联提供了有力工具。 ube3a与fmr1突变模型：这两种基因分别与Angelman综合征和脆性X综合征相关，两者均表现出ASD样行为特征。日本新潟大学团队利用斑马鱼模型结合RNA测序技术，深入分析了焦虑样行为相关的分子通路，揭示了不同基因突变所致行为表型的差异性。 napb敲除模型：2025年发表于《Scientific Reports》的研究构建了NAPB基因敲除斑马鱼，发现该模型表现出运动神经元轴突缩短、过度活跃和癫痫样行为，成功模拟了ASD与癫痫共病的临床表型。电生理分析表明，其癫痫表型源于大脑区域神经超兴奋性，而非突触传递缺陷。 2.2 化学诱导模型 除基因编辑模型外，丙戊酸（VPA）诱导的ASD斑马鱼模型也被广泛应用。VPA是一种抗癫痫药物，孕期暴露可显著增加子代患ASD的风险。2025年发表于《Cells》的系统综述对VPA诱导的成年斑马鱼ASD模型进行了全面分析，系统总结了不同VPA剂量对ASD样表型的诱导效果。研究表明，在胚胎发育关键窗口期暴露于VPA，可稳定诱导出持久、长程的ASD样行为表型，包括社交障碍和重复刻板行为。 三、基于斑马鱼的药物研发进展 3.1 高通量药物筛选平台 斑马鱼模型最显著的应用价值之一在于其与高通量筛选技术的深度融合。耶鲁大学团队建立的520种FDA药物行为特征数据库，为ASD药物发现提供了宝贵的公共资源。该研究采用以下研究范式： 行为表型数据库构建：通过高通量测定520种药物对斑马鱼幼虫基础感觉处理和觉醒行为的影响，建立系统的药物行为特征数据库； 基因-药物反向关联分析：将9个ASD高风险基因突变体的行为特征与药物行为特征进行关联分析，识别出与ASD基因突变体行为表型呈反向相关的药物机制； 候选药物验证：在SCN2A和DYRK1A突变体中进行筛选验证，鉴定出雌激素受体激动剂雌酮哌嗪（针对scn1lab突变）、微管抑制剂紫杉醇（针对dyrk1a突变）和线粒体调节剂左卡尼汀（对两种突变体均有效）； 跨物种验证：左卡尼汀在携带相同突变的人类干细胞分化谷氨酸能神经元中同样恢复信号传导缺陷，验证了药物作用的跨物种保守性。 3.2 靶向肠-脑轴的干预策略 肠-脑轴功能紊乱被认为是ASD的重要病理机制之一。2026年发表于《The ISME Journal》的研究利用Katnal2突变斑马鱼模型，系统评估了粪菌移植和嗜黏蛋白阿克曼菌（Akkermansia muciniphila）补充对神经发育缺陷的改善作用。研究发现： 野生型供体粪菌移植和A. muciniphila补充显著改善了Katnal2突变体的孵化率、生长参数、心率和运动能力； A. muciniphila成功定植肠道，重塑了肠道菌群结构，降低了焦虑样行为； 机制研究表明，A. muciniphila通过上调多巴胺（th）、5-羟色胺（tph1a）和GABA合成相关基因的表达，下调5-羟色胺受体htr3a，并增强短链脂肪酸受体ffar2的表达，从而发挥神经调节作用。 这一研究为基于益生菌的ASD干预策略提供了实验依据，展示了斑马鱼在菌群-肠-脑轴研究中的独特价值。 3.3 药物作用机制研究 斑马鱼模型的透明特性使药物作用机制的研究更加直观。以slc6a3敲除模型为例，转录组学分析揭示了多巴胺系统功能障碍引发的广泛基因表达变化，为理解ASD的分子病理机制提供了新视角。 在抗精神病药物评价方面，研究证实利培酮（risperidone）和氯氮平（clozapine）可改善slc6a3突变斑马鱼的运动功能、社交互动和焦虑水平，其中利培酮显示出更优的治疗效果。这些发现为临床药物在ASD治疗中的再定位提供了实验依据。 四、权威背书与研究展望 4.1 国际顶级期刊的广泛认可 斑马鱼模型在ASD药物研发领域的应用价值已获得国际学术界的广泛认可。相关研究成果发表于《美国国家科学院院刊》（PNAS）、《The ISME Journal》、《Translational Psychiatry》、《Cells》、《Scientific Reports》和《Neuropharmacology》等权威期刊。这些研究涵盖了从基因编辑模型构建、高通量药物筛选到机制研究的完整链条，共同构成了斑马鱼ASD药物研发的方法学体系。 4.2 转化前景与挑战 尽管斑马鱼模型优势显著，研究者也清醒地认识到其局限性。斑马鱼与哺乳动物在部分器官结构上存在差异（如缺乏大脑皮层），某些复杂行为难以完全复现，非水溶性化合物的给药方式仍存在技术挑战。因此，斑马鱼模型通常被定位为药物研发链条中的“第一道筛选关卡”，其研究结果仍需在哺乳动物模型和人类来源的细胞模型中进行验证。 值得注意的是，PNAS研究的一个重要创新点在于，其发现的候选药物左卡尼汀不仅在斑马鱼突变体中有效，还在携带相同突变的人类神经元中验证了效果。这一研究范式——斑马鱼高通量筛选与人类细胞模型验证相结合——为加速ASD药物转化提供了可复制的路径。 结语 斑马鱼模型凭借其遗传保守性、实验可操作性和高通量筛选潜力，已发展成为孤独症药物研发的重要平台。从基因编辑模型的精准构建，到520种药物的大规模行为筛选，再到靶向肠-脑轴的干预策略，斑马鱼正在连接基础研究与临床转化之间的关键环节。随着标准化体系的持续完善及与人类干细胞模型、类器官模型的多维整合，斑马鱼将在ASD精准药物筛选中发挥日益重要的作用，为这一复杂疾病的治疗带来新的希望。 参考文献 [1] Jia PP, et al. Fecal microbiota transplantation and Akkermansia muciniphila restore neurodevelopment and behavior via the gut-brain axis in autism-like zebrafish. ISME J. 2026. PMID: 41910195. [2] Jamadagni P, et al. Pharmaco-behavioral profiling identifies suppressors of autism gene-associated phenotypes in zebrafish. Proc Natl Acad Sci USA. 2026;123(12):e2518846123. [3] Valproate-Induced Model of Autism in Adult Zebrafish: A Systematic Review. Cells. 2025;14(2):109. [4] Dougnon G, et al. Behavioral and molecular insights into anxiety in ube3a and fmr1 zebrafish models of autism spectrum disorders. Transl Psychiatry. 2025;15(1):512. [5] Shin KC, et al. Seizure-like behavior and hyperactivity in napb knockout zebrafish as a model for autism and epilepsy. Sci Rep. 2025. [6] Li W, et al. Dopamine disruption and autism phenotypes in slc6a3−/− zebrafish: Behavioural and molecular insights. Neuropharmacology. 2025. 青岛市斑马鱼生物创新专家工作站 青岛奔月斑马鱼实验室，依托与北京中医药大学中药学院、山东省科学院生物研究所等国内顶尖科研单位建立的深度战略合作，致力于打造国内领先的斑马鱼生物活性评价服务平台。 服务领域：产品应用覆盖大健康产业、功能性食品、保健食品、化妆品、医药研发、医学研究及动物保健品等多个领域，提供从实验设计、模型构建、数据分析到结果解读的一站式实验解决方案，助力客户加速产品研发进程。

Roluperidone has been de-risked by consistent positive results in two prior pivotal trials and remains the only late-stage drug candidate for this high-need population Efficacy topline data expected 2H 2027 BURLINGTON, Mass., March 31, 2026 (GLOBE NEWSWIRE) -- Minerva Neurosciences, Inc. (Nasdaq: NERV), a clinical-stage biopharmaceutical company focused on the development of therapies to treat central nervous system disorders, today announced that the first patient has been screened in its global, confirmatory Phase 3 clinical trial evaluating roluperidone as monotherapy for the treatment of negative symptoms of schizophrenia. Negative symptoms, including avolition (severe lack of motivation), anhedonia (inability to experience pleasure) and social withdrawal can lead to profound personal and functional impairment and represent one of the greatest unmet needs in schizophrenia. There are currently no FDA-approved treatments with this indication. The Phase 3 trial will enroll approximately 380 patients across roughly 40 clinical sites worldwide, including the United States (US) and multiple European countries. This confirmatory Phase 3 trial follows productive discussions with the FDA on the overall design and efficacy assessments. It builds directly on Minerva’s clinical success in the prior pivotal Phase 2b and Phase 3 trials (C03 and C07), both of which demonstrated consistent improvements in negative symptoms with the 64 mg dose of roluperidone. “Initiation of this confirmatory Phase 3 trial is an important milestone for Minerva and for patients living with persistent and impairing negative symptoms of schizophrenia,” said Dr. Remy Luthringer, Executive Chairman and CEO of Minerva Neurosciences. “With no approved treatments for this indication in the US, roluperidone remains the only late-stage candidate in development for this population. The study builds directly on our prior experience showing consistent results across the two earlier trials and our execution strategy gives us confidence in our timelines.” “Patients with schizophrenia often live with persistent negative symptoms such as avolition and anhedonia - challenges that remain even when positive symptoms are controlled with current therapies,” said Dr. Elan Cohen, Principal Investigator at CenExel Marlton, New Jersey and Lead Coordinating Investigator for the trial. “By evaluating roluperidone in a population with stable positive symptoms, this trial isolates its potential to improve these core drivers of disability while laying the groundwork for a broader treatment strategy. Strengthening motivation, cognition, and functioning may ultimately support more comprehensive symptom control over time, and the consistency seen in prior studies makes this confirmatory Phase 3 trial especially compelling.” About the Phase 3 MIN-101C19 Trial The global Phase 3 MIN-101C19 trial will enroll approximately 380 adults aged 18–55 with moderate to severe negative symptoms of schizophrenia, confirmed by a Positive and Negative Syndrome Scale (PANSS) negative subscale score greater than 20 and stable positive symptoms for at least six months. The trial utilizes a two-part design. The overall objective of the study is to confirm the effect of roluperidone on primary negative symptoms at 12 weeks compared to placebo and to evaluate longer-term relapse of positive symptoms compared with commonly prescribed antipsychotic medications for an additional 40 weeks. The trial is designed to minimize variability and maximize sensitivity to treatment effect, including standardized assessments, and comprehensive caregiver engagement. Topline data from the 12-week Phase A portion (i.e., primary efficacy endpoint) of the trial are expected in the second half of 2027. The trial’s operational model includes intensive rater training, real-time monitoring of scoring data, and structured caregiver outreach to support safety tracking, functional assessments, and adherence. Phase A is a12-week, randomized, double-blind, placebo-controlled phase during which patients will receive 64 mg of roluperidone or placebo to evaluate the primary endpoint: change from baseline in the Marder Negative Symptoms Factor Score (NSFS), which is a factor-analytic composite created from selected PANSS items. The sole key secondary endpoint is the change from baseline in the Personal and Social Performance (PSP) total score. Other secondary endpoints include a broad set of additional clinical measures, including PANSS subscales, Clinical Global Impression – Severity (CGI-S), Clinical Global Impression – Improvement (CGI-I), the Calgary Depression Scale, avolition-specific analyses, and patient and caregiver treatment-satisfaction ratings. Phase B extends the trial for 40 weeks using a double-dummy, active-controlled, randomized design comparing continued roluperidone with three commonly prescribed antipsychotic medications (risperidone, aripiprazole, or olanzapine). This phase is designed to compare relapse rates between treatment groups. Relapses of positive symptoms will be evaluated using a rigorous, multi-component definition incorporating psychometric endpoints based on PANSS score worsening, and clinically meaningful events such as hospitalization or dangerous behavior. About Minerva Neurosciences Minerva Neurosciences, Inc. is a clinical-stage biopharmaceutical company focused on developing product candidates to treat CNS diseases. Minerva’s goal is to transform the lives of patients with improved therapeutic options, including roluperidone for negative symptoms of schizophrenia. For more information, please visit the Company’s website . Forward-Looking Safe Harbor Statement This press release contains forward-looking statements which are subject to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, reflect management’s expectations as of the date of this press release, and involve certain risks and uncertainties. Forward-looking statements include, but are not limited to, statements herein with respect to implied or express statements regarding the anticipated clinical benefits and market opportunities associated with roluperidone, including its potential to address clinical and regulatory challenges; and the expected timeline, design, and conduct of Minerva’s Phase 3 trial of roluperidone. These forward-looking statements are based on our current expectations and may differ materially from actual results due to a variety of factors including, without limitation, trials and studies may be delayed and may not have satisfactory outcomes, and earlier trials and studies may not be predictive of later trials and studies; the design and rate of enrollment for clinical trials, including the current design of the confirmatory Phase 3 trial evaluating roluperidone may not enable successful completion of the trial(s); the commercial opportunity for roluperidone in negative symptoms of Schizophrenia may be smaller than anticipated; Minerva may be unable to obtain and maintain regulatory approvals; Minerva may experience uncertainties inherent in the initiation and completion of clinical trials and clinical development; Minerva’s future financial performance and position may not improve, resulting in difficulties in implementing Minerva’s business strategy, and plans and objectives for future operations; the expected sufficiency of Minerva’s existing cash resources and runway may not be accurate resulting in the need for additional financing sooner than anticipated or unexpected liquidity constraints; the internal and external costs required for Minerva’s ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected, which may cause the company to use cash more quickly than expected or to change or curtail some of Minerva’s plans or both; the need to align with collaborators or partners may hamper or delay development and regulatory efforts or increase costs; uncertainties of patent protection and litigation; general economic conditions; and other factors that are described under the caption “Risk Factors” in Minerva’s filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2025, filed with the Securities and Exchange Commission. Copies of reports filed with the SEC are posted on Minerva’s website at The forward-looking statements in this press release are based on information available to the Company as of the date hereof, and the Company disclaims any obligation to update any forward-looking statements, except as required by law. Contacts: Investor inquiries: Frederick Ahlholm Chief Financial Officer Minerva Neurosciences, Inc. info@minervaneurosciences.com Corey Davis, Ph.D. LifeSci Advisors, LLC 212-915-2577 cdavis@lifesciadvisors.com