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★ 点击上方“听全文”解放双手 2025年11月7日，美国肝病研究学会(AASLD)年度大会 The Liver Meeting 2025 在美国•华盛顿会议中心正式召开。会议汇聚肝病研究领域的最新科研硕果与前沿探索方向，为全球参会者精心构筑一个深化肝病理论认知、拓展专业视野边界的学术交流殿堂。 为助力广大读者精准捕捉会议的学术精髓，及时洞悉领域前沿动态，肝胆相照平台特别甄选会议摘要中的热点研究内容，本篇专题报道聚焦“遗传代谢性肝病”这一关键领域，为广大同仁提供最新研究进展。 2025 AASLD 遗传代谢性肝病 热点研究汇总 一 0073 硫代钼酸胆碱治疗威尔逊病患者可快速改善铜平衡 RAPIDLY IMPROVED CU BALANCE IN WILSON DISEASE PATIENTS ON TIOMOLYBDATE CHOLINE 作者：Aftab Ala¹，Thomas Sandahl²，Anna Czlonkowska³，Chandler Robinson⁴，Andrew Cittadine⁴，Valentina Medici⁵，Karl Heinz Weiss⁶，Frederick Askari⁷ ¹Kings College Hospital, ²Aarhus University Hospital, ³Institute of Psychiatry and Neurology, ⁴Monopar Therapeutics, ⁵University of California Medical Center, ⁶Stadtmission Heidelberg, ⁷University of Michigan Medical Center 背景 威尔逊病（Wilson disease，WD）是一种罕见的常染色体隐性遗传病，由P型ATP酶铜转运蛋白ATP7B基因突变引发，导致铜（Cu）在肝脏与脑组织中异常蓄积。硫代钼酸胆碱（TiomolybdateCholine，TMC）是一款处于研发阶段的口服每日一次铜结合剂，拟用于WD治疗。目前临床应用的口服铜螯合剂存在疗效有限、常诱发神经症状加重、可能引发潜在严重不良反应及需每日多次给药等问题，临床需求尚未得到充分满足。 Background：Wilson disease (WD) is a rare autosomal recessive disorder caused by copper (Cu) accumulation in the liver and brain due to mutations in the P-type ATPase Cu transporter ATP7B. Tiomolybdate choline (TMC) is an oral once-daily Cu-binding agent being investigated for the treatment of WD. The current oral chelators for WD present a less than satisfactory treatment in WD patients as they can cause neurological worsening, potential debilitating side effects, and have multiple-times-per-day dosing regimens. 方法 本研究为开放性、单臂II期临床试验，旨在评估每日一次重复给药TMC对WD患者铜平衡、安全性及耐受性的影响。通过收集患者铜摄入（食物、饮水）与排出（粪便、尿液）样本并测定铜含量，量化评估患者铜平衡状态。研究设计包含1个治疗前基线期（第-4至-1天）与2个治疗期（第1–28天、第25–39天）：第一治疗期（第1–28天）患者每日口服TMC15mg；自第29天起进入第二治疗期，剂量增至30mg/天，若出现丙氨酸氨基转移酶（ALT）升高，则调整为隔日口服15mg。 Methods：This open-label, single-arm Phase 2 trial evaluated the effect of once-daily repeat-dose TMC on Cu balance, safety, and tolerability in patients with WD. To determine Cu balance, patient intake (food and drink) and output (feces and urine) were collected and analyzed for Cu content during a pre-treatment baseline period (study days -4 through -1) and two treatment periods (study days 1–8 and 25–39). In the first treatment period, patients received 15 mg/day. In the second treatment period, the dose was increased to 30 mg/day on study day 29, except in patients who experienced an elevation in alanine aminotransferase (ALT) and were reduced to 15 mg every other day..  结果 研究共入组9例WD患者，其中1例因违反试验方案（未停用青霉胺）提前退出，其余8例完成全部试验。在TMC15mg/天治疗期（第1–28天）及整个研究周期（第1–39天）内，完成试验患者的累计每日平均铜平衡较基线显著下降，提示TMC可有效改善铜排泄；进一步分析显示，铜平衡改善主要源于粪便铜排泄量增加。 安全性评估结果显示：实验室检查指标、生命体征、体格检查及心电图均未观察到具有临床意义的异常；期间出现的ALT升高均为1级或2级，经剂量调整后可恢复正常；整个试验未报告严重不良事件或死亡病例，亦无患者因治疗相关不良事件（TEAEs）停用TMC。 Results：A total of 9 WD patients were enrolled. One patient discontinued the study early due to a protocol violation (failure to discontinue penicillamine treatment). In the 8 who completed the study, the cumulative mean daily Cu balance was statistically significantly lower compared to pre-treatment baseline during the TMC 15 mg/day period (days 1–28) and during the whole study period (days 1–39). This improvement was due to increased fecal Cu excretion with TMC treatment. No clinically significant changes were observed in laboratory parameters, vital signs, physical examinations, or ECG results. Any elevations in ALT that occurred were grade 1 or 2 and reversible with dose modulation. No serious adverse events or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to TMC discontinuation. 结论 TMC治疗可通过增加粪便铜排泄，快速且持续地改善WD患者每日铜平衡状态，且未发现显著安全性风险，所有不良事件均具有可逆性。结合欧洲肝脏研究学会（EASL）2025年公布的TMC长期疗效与安全性数据，本研究的关键铜平衡试验结果表明，TMC或可为WD患者带来临床获益，同时有望成为未来WD早期药物研发的参考模型。 Conclusion：TMC treatment resulted in a rapid and persistent improvement in daily Cu balance, due to increased fecal excretion of Cu. No significant safety issues were identified, and all TEAEs were reversible. Combined with the long-term efficacy and safety data presented at EASL 2025, the results from this key Cu balance trial indicate that TMC may provide meaningful clinical benefit in WD patients and could serve as a possible future model for early-stage drug development programs in WD. 二 3628 威尔逊病患者的认知功能：来自威尔逊病注册研究的前瞻性分析 COGNITIVE FUNCTION IN PATIENTS WITH WILSON DISEASE: PROSPECTIVE ANALYSIS FROM THE WILSON DISEASE REGISTRY STUDY 作者：Michael Schilsky¹、Asim Ulcay¹、Hatice Maras¹、Sefa Keserci¹、Amar Patel¹、Susan Rubman¹、Regino Gonzalez-Peralta²、Isabelle Mohr³、Ayse Coskun⁴、Uyen To¹、Kaitlin Maciejewski⁵、Yanhong Deng⁵、Zoe Mariño Méndez⁶、Paula Zimbrean¹ ¹Yale University Medical Center, ²AdventHealth for Children, ³University Hospital Heidelberg, Germany, ⁴Creighton University, Omaha, Nebraska, ⁵Yale University, ⁶Hospital Clinic of Barcelona, Spain 研究背景 目前评估威尔逊病（WD）患者认知功能的前瞻性数据较为缺乏。蒙特利尔认知评估量表（MOCA）是一款涵盖多个认知领域且具备标准化评分体系的认知功能评估工具，其总分为 30 分，其中 < 26 分判定为认知功能异常，≥26 分判定为认知功能正常。 Background：Few prospective data are available to assess cognition in patients with Wilson disease (WD). The Montreal Cognitive Assessment (MOCA) is used to evaluate cognitive function and includes several domains with standardized scoring. The total score is 30, with <26 considered abnormal and ≥26 indicating normal cognition. 研究目的 本研究旨在评估纳入威尔逊病注册研究（WDR）的 WD 患者在入组时及随访期间的认知功能状态。 Aims: To evaluate cognitive function in WD patients enrolled in the Wilson Disease Registry (WDR) study using baseline and longitudinal follow-up data. 研究方法 对WDR中的成年WD患者开展横断面（入组时）及纵向认知功能评估，采用MOCA量表及神经功能评分（UWDRS）作为评估工具。根据患者初诊时的病史，将其分为无症状型、肝型及神经型三种表型。对重复测量的MOCA数据采用线性混合模型（ANCOVA）进行分析，将时间作为主要混杂因素；所有变量均以“均数（标准差）”形式呈现。 Methods： Cross-sectional (at study entry) and longitudinal assessments of adult WD patients from the WDR were performed using MOCA and neurological (UWDRS) evaluations. Patients were categorized as asymptomatic, hepatic, or neurologic based on disease presentation at diagnosis. Repeated MOCA measurements were analyzed using linear mixed models (ANCOVA), controlling for time as the main confounder. Data were expressed as mean (standard deviation).  研究结果 研究共纳入138例WD患者，其中女性占51%，平均年龄为39±14岁，平均确诊时间为15.8±15年。表型分布情况为：肝型47%、神经型39%、无症状型14%。 基线时患者MOCA平均得分为26.3±3.1分，其中44例（32%）患者MOCA得分<26分（平均22.9±3.0分），各表型认知异常占比分别为：无症状型21%、肝型30%、神经型37%。 Pearson相关分析显示，基线MOCA评分与UWDRS评分呈负相关（r=-0.47，p<0.001），且MOCA得分<26分的患者，其UWDRS评分显著更高（p=0.0003）。 整体来看，从入组至第2年、第3年，患者MOCA评分平均提高1分（均p=0.001），提示治疗可能对认知功能具有改善作用。纵向分析结果显示，经基线MOCA评分校正后，仅基线MOCA得分<26分的患者在随访第2-5年期间，认知功能呈现显著改善（均p<0.01），且每年平均提高至少1分；进一步按表型校正后，仅肝型患者的MOCA评分出现显著改善，提升幅度为0.6-1.8分。 Results：The cohort included 138 patients (51% female), with a mean age of 39 (±14) years and a mean duration since diagnosis of 15.8 (±15) years. Phenotypes included hepatic (47%), neurologic (39%), and asymptomatic (14%). At baseline, the mean MOCA score was 26.3 (±3.1), with 44 (32%) patients scoring <26 [mean 22.9 (±3)] (asymptomatic 21%, hepatic 30%, neurologic 37%). Baseline MOCA scores were negatively correlated with UWDRS (r = -0.47, p < 0.001, Pearson). Patients with MOCA <26 had significantly higher UWDRS scores (p = 0.0003). On average, MOCA scores increased by 1 point between enrollment and years 2 and 3 (both p = 0.001), suggesting cognitive improvement with treatment. In longitudinal analysis, adjusted for baseline MOCA, only those with initial MOCA <26 showed significant improvement over time (years 2–5, all p < 0.01), with at least a 1-point annual increase. When adjusted for phenotype, only the hepatic group showed significant MOCA improvement, ranging from +0.6 to +1.8 compared to baseline. 研究结论 MOCA量表可有效检测并量化WD患者的认知损伤程度。尽管多数WD患者认知功能正常（MOCA≥26分），但认知受损患者（MOCA<26分）的UWDRS评分显著更高，提示其中枢神经损伤更严重，该现象在神经型患者中尤为突出。此外，WD患者认知功能随时间推移显著改善，这一结果强调了早期诊断与规范治疗对改善WD患者预后的重要性。 Conclusion：MOCA effectively detected and quantified cognitive impairment in WD patients. While most patients maintained normal cognition (MOCA ≥26), those with impairment (MOCA <26) exhibited a strong negative correlation with UWDRS scores, indicating greater CNS injury in neurologically affected individuals. The observed cognitive improvement over time underscores the importance of early diagnosis and treatment in optimizing WD patient outcomes. 三 637 国际 Ⅰ/Ⅱ 期 GATEWAY 基因治疗试验中期结果：VTX-801 在成人肝豆状核变性患者中的临床研究 INTERIM RESULTS OF THE INTERNATIONAL PHASE I/II GATEWAY GENE THERAPY TRIAL WITH VTX-801 CONDUCTED IN ADULT PATIENTS WITH WILSON DISEASE 作者：Michael Schilsky¹、Frederick Askari²、Thomas Sandahl³、William Lee⁴、Aftab Ala⁵、Regino Gonzalez-Peralta⁶、Valentina Medici⁷、Sean Rudnick⁸、Ulrich Lauer⁹、Christoph Berg¹⁰、Hartmut Schmidt¹¹、Sonia Valero¹²、Jean Philippe Combal¹³、Gloria Gonzalez-Aseguinolaza¹⁴、Lorenzo D'Antiga¹⁵、Bernard Benichou¹³ ¹Yale University Medical Center, ²University of Michigan Medical Center, ³Aarhus University Hospital, ⁴University of Texas Southwestern Medical Center, ⁵Kings College Hospital, ⁶AdventHealth for Children, ⁷University of California Medical Center, ⁸Atrium Health Wake Forest Baptist, ⁹Medical University Hospital Tuebingen, Germany, ¹⁰Medical University Hospital, Tuebingen, Germany, ¹¹University of Essen, Germany, ¹²Vivet Therapeutics, Paris, France, ¹³Vivet Therapeutics, Paris, France, ¹⁴Vivet Therapeutics SL, Pamplona, Spain, ¹⁵University of Bergamo, Italy 背景 肝豆状核变性（Wilson 病，WD）是由ATP7B铜转运基因致病变异引发的铜稳态障碍性遗传代谢病。该突变会导致胆汁铜排泄功能受损，造成肝脏及其他组织铜蓄积，并伴随血清铜蓝蛋白（ceruloplasmin,Cp）水平降低。目前临床常用的WD治疗方案存在副作用多、患者依从性差等问题，严重影响长期疗效与患者生存质量。 VTX-801是一种重组腺相关病毒（rAAV）载体，携带经缩短的ATP7B基因（miniATP7B），且由肝脏特异性启动子驱动其表达。此前在6–12周龄WD小鼠模型中的研究显示，VTX-801治疗可恢复小鼠胆汁铜排泄功能、升高血浆Cp水平、降低肝脏铜含量、改善肝组织学表现，并实现100%长期生存。 Background：Wilson Disease (WD) is a disorder of copper (Cu) homeostasis due to pathogenic variants in the ATP7B copper-transporter gene that impair biliary Cu excretion and cause tissue Cu accumulation and reduced circulating ceruloplasmin (Cp). Limitations of management include treatment side effects and poor adherence affecting long-term outcomes and survival. VTX-801 is a recombinant adeno-associated viral vector (rAAV) carrying a shortened ATP7B gene with a liver-specific promoter. Previous studies with VTX-801 in 6–12-week-old WD mice demonstrated restoration of biliary Cu excretion, increased levels of plasma Cp, reduced liver Cu, improved hepatic histology, and 100% long-term survival. 方法 GATEWAY试验是一项国际多中心、Ⅰ/Ⅱ期、开放标签、单次递增给药且随访期长达5年的临床研究（临床试验登记号：NCT04537377），旨在成人WD患者中评估VTX-801的安全性、药效学特征及疗效。本研究通过64Cu药代动力学分析，分别在VTX-801输注后3个月和9个月评估患者的治疗反应。 Methods：GATEWAY is an international phase I/II, open-label, 5-year follow-up, single dose-escalation study of VTX-801 in adults with WD (NCT04537377). This first-in-human study assessed safety, pharmacodynamics, and efficacy of VTX-801. VTX-801 response at 3 or 9 months post-infusion was based upon 64Cu pharmacokinetic assessments.  结果 研究共设两个剂量组：低剂量组（Cohort1，n=2）已完成给药，中剂量组（Cohort2，n=2）仍在治疗中。 安全性方面：共报告1例严重不良事件（药物性肝损伤，DILI）；2例患者出现输注相关反应，经对症处理后缓解；所有4例患者在VTX-801输注后均出现轻度、可逆性丙氨酸氨基转移酶（ALT）升高，且未对整体肝功能造成显著影响。其中，Cohort1中1例患者ALT轻度升高至104IU/L；Cohort2中1例患者ALT升高至245IU/L，符合DILI诊断标准，遂行肝活检，两者经口服糖皮质激素治疗后均迅速恢复。 疗效与药效学方面：总体而言，VTX-801治疗后的疗效反应未达预期，患者仍需维持标准治疗，未实现标准治疗停用。1年随访时的肝活检结果显示：Cohort1患者约50%的肝细胞可检测到miniATP7BmRNA表达；Cohort2中发生DILI的患者因非计划肝活检发现，其肝细胞miniATP7BmRNA表达比例高达75%。目前两组患者的完整药效学数据仍在整理中。 Results：VTX-801 Cohort 1 (low dose) was completed (N=2 patients), and Cohort 2 (intermediate dose) was treated (N=2). One SAE was reported (DILI). Two patients had infusion-associated reactions managed with symptomatic treatment. All four had mild, resolving ALT increases following VTX-801 infusion without affecting liver function. One in Cohort 1 had a delayed, mild ALT elevation to 104 IU/L, and one in Cohort 2 had ALT elevation to 245 IU/L meeting criteria for DILI and had a liver biopsy; both resolved rapidly with a course of oral steroid treatment. Overall, insufficient VTX-801 response was observed, and standard of care treatment was not withdrawn. Follow-up liver biopsy at 1 year in a patient from Cohort 1 showed miniATP7B mRNA expression in up to 50% of hepatocytes, and an unscheduled biopsy after DILI in the Cohort 2 patient showed miniATP7B mRNA expression in up to 75% of hepatocytes. Available pharmacodynamic data for Cohorts 1 and 2 will be presented. 结论 本研究证实，采用AAV载体向人肝脏递送ATP7B基因具有可行性；VTX-801能够成功转导人肝细胞，但尚未使患者铜代谢相关指标（如胆汁铜排泄、血清Cp水平）的改善达到临床治疗水平。未来需进一步研究影响功能性外源基因（miniATP7B）表达程度的关键因素，以及其在促进胆汁铜排泄、提升血清铜蓝蛋白水平方面的潜在能力，为优化WD基因治疗方案提供依据。 Conclusion： Delivery of ATP7B is possible in human liver using AAV. VTX-801 transduction was successful, however, changes in Cu parameters were subtherapeutic. Further study is needed to understand factors affecting the degree of functional transgene expression and its ability to increase biliary copper excretion and Cp levels in humans. 整理 | 肝胆相照平台 参考 | 大会官网 ▼ 关注“肝胆相照平台”获取更多大会讯息，文末点击“阅读全文”进入大会官网 *本文仅供医疗卫生专业人士为了解资讯使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议。如该等信息被用于了解资讯以外的目的，平台及作者不承担相关责任。 *封面：大会官网/创客贴(素材/字体已有授权) 听说点赞的人功德+999 🧡点一下，好运连连！