A Single-center Registry and Embedded Interventional Study of the Effects of COVID-19 With and Without Treatment With AT-001 on Cardiac Structure and Function in Patients Hospitalized for Management of COVID-19 Infection

Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway, a trigger of the inflammatory cascade. The study team hypothesizes that aldose reductase inhibition with AT-001 (caficrestat) might represent a novel therapeutic approach to reduce inflammation and risk of adverse outcomes in diabetic patients with COVID-19.
An open-label pilot study to assess safety, tolerability and efficacy of AT-001 in hospitalized COVID-19 patients with history of diabetes mellitus and heart disease will be conducted. Eligible participants will be treated with AT-001 1500 mg twice daily for up to 14 days. Safety, tolerability, survival and length of hospital stay data were compared with matched controls from a contemporaneous registry of COVID-19 patients.

开始日期2020-04-08

申办/合作机构

NYU Langone Health

NCT03199469

/ Active, not recruiting临床2/3期

ASPIRO: A Phase 1/2/3, Randomized, Open-Label, Ascending-Dose, Delayed-Treatment Concurrent Control Clinical Study to Evaluate the Safety and Efficacy of AT132, an AAV8-Delivered Gene Therapy in X-Linked Myotubular Myopathy (XLMTM) Patients

X-linked myotubular myopathy (XLMTM) is a rare and serious condition present at birth where the muscles do not work properly. There are currently no therapies for this serious condition.
The protein myotubularin is needed for muscle development and movement. A gene called MTM1 tells the body to make myotubularin. XLMTM is caused by changes, or mutations, in the MTM1 gene. Changes in the MTM1 gene causes low levels of myotubularin to be made, so the muscles do not work properly. XLMTM may also affect the liver, and in some cases, this can be dangerous and threaten the patient´s life.
Gene therapy is a way of getting a healthy copy of a gene into the body. This allows the body's cells to make a normal protein that may reduce disease symptoms. AT132 is a gene therapy that gets a healthy MTM1 gene into the body to help improve muscle development and function in young children with the disease. AT132 does not treat liver disease, and because of the way the treatment works, it may make liver problems worse.
AT132 was the gene therapy treatment given to children who participated in this study and is not available to the public. In this study, AT132 was given to children for the first time. Due to the occurrence of severe complications and fatalities associated with administration of AT132, the study has been stopped and no further participants will be enrolled.
The main aim of the study is to check how long young children need machines to support breathing (ventilation support) after AT132.
Due to the occurrence of severe complications and fatalities associated with administration of AT132, the study has been stopped and no further participants will be enrolled. This study included children with XLMTM under 5 years old who had breathing problems caused by XLMTM. They couldn't take part if they were born prematurely, recently had surgery, had liver disease or other condition or disease the study doctor thought was medically important. The study did enroll participants with medically significant liver disease.
This is an open-label study. This means that young children and their caregivers, and clinic staff know that young children received AT132. This study was designed with 2 parts and is now in a long-term follow-up phase to collect information on the safety and improvements in muscle function in the children who received AT132.
In Part 1, small groups of young children were given different doses of AT132, with one group receiving a lower dose and one group receiving a higher dose of AT132. The purpose of giving the two doses was to determine which dose was best for treating the muscle disease. After receiving AT132, a medical panel of experts reviewed each child for safety and for how their muscles responded. AT132 did not demonstrate appropriate safety at either dose. Administration of AT132 was stopped. Children who received AT132 are being monitored for 10 years for safety and to understand how their muscles function over time.

开始日期2017-08-02

申办/合作机构

Astellas Gene Therapies, Inc.

NCT01731093

/ Completed临床1期

Multiple-ascending Dose Clinical Trial of the Safety and Tolerability of Antioxidant (AT-001) Treatment for Reducing Brain Oxidative Stress

The purpose of this study is to determine the safety, bioavailability, and effectiveness of an organic yeast-selenium compound in reducing brain oxidative stress. Oxidative stress in the brain has been linked to a variety oif disorders including Alzheimer's disease. Selenium is a very powerful antioxidant that could prove useful in reducing the harmful effects of oxidative stress in the brain and may help prevent diseases such as Alzheimer's. Our recent work has demonstrated that the specific type of selenium compound greatly influences it's ability to enhance brain health and prevent Alzheimer changes in mouse models of this disease.
This study will enroll 24 participants and will allow us to test the hypotheses that yeast-selenium supplementation is safe in the elderly, and that our specific formulation reduces brain oxidative stress.

开始日期2012-03-01

申办/合作机构

Alltech Life Sciences Inc.

100 项与 Resamirigene Bilparvovec 相关的临床结果

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100 项与 Resamirigene Bilparvovec 相关的转化医学

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100 项与 Resamirigene Bilparvovec 相关的专利（医药）

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项与 Resamirigene Bilparvovec 相关的文献（医药）

2024-01-01·EBioMedicine

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial

Article

作者: Meng, Hui ; Sepulveda, Bryan ; Smith, Barbara K ; Conner, Edward ; Prom, Mariah J ; Dowling, James J ; Kuntz, Nancy L ; Lawlor, Michael W ; Schoser, Benedikt ; Neuhaus, Sarah ; Blaschek, Astrid ; Seferian, Andreea M ; Margeta, Marta ; Sewry, Caroline A ; Vanden Avond, Mark ; Kumar, Suresh N ; James, Emma S ; Rico, Salvador ; Shieh, Perry B ; Danielson, Susan ; Tsuchiya, Etsuko ; Müller-Felber, Wolfgang ; Sadhu, Chanchal ; Ott, Emily ; Saade, Dimah N ; Krakau, Paul ; Beatka, Margaret ; Jones, Karra A ; Bönnemann, Carsten G ; Varfaj, Fatbardha ; Christensen, Sarah ; Prasad, Suyash ; Wells, Clive ; Foley, A Reghan ; Qasim, Ummulwara R ; Miller, Weston ; Gordish-Dressman, Heather ; Beggs, Alan H ; Lee, Jun

BACKGROUND:

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated.

METHODS:

Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed.

FINDINGS:

Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants.

INTERPRETATION:

Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study.

FUNDING:

Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

2023-12-01·The Lancet. Neurology

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial

Article

作者: Kuntz, Nancy L ; Müller-Felber, Wolfgang ; Smith, Barbara K ; Bönnemann, Carsten G ; Servais, Laurent ; Varfaj, Fatbardha ; Childers, Martin K ; Miller, Weston ; Neuhaus, Sarah ; Alfano, Lindsay N ; Lawlor, Michael W ; Muntoni, Francesco ; Beggs, Alan H ; Buj-Bello, Ana ; Shieh, Perry B ; Rico, Salvador ; Han, Cong ; Mavilio, Fulvio ; Blaschek, Astrid ; Lee, Jun ; MacBean, Vicky ; Murtagh, Michael ; Foley, A Reghan ; Graham, Robert J ; Prasad, Suyash ; Saade, Dimah N ; Noursalehi, Mojtaba ; Seferian, Andreea M ; Dowling, James J ; Duong, Tina ; James, Emma S ; Jain, Minal ; Coats, Julie

BACKGROUND:

X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1.

METHODS:

ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 10¹⁴ vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 10¹⁴ vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated.

FINDINGS:

Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure).

INTERPRETATION:

Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing.

FUNDING:

Astellas Gene Therapies.

2023-10-01·American journal of human genetics

High-throughput transcriptome analyses from ASPIRO, a phase 1/2/3 study of gene replacement therapy for X-linked myotubular myopathy

Article

作者: Varfaj, Fatbardha ; Lakshman, Neema ; Romano, Oriana ; Mavilio, Fulvio ; Sefid-Dashti, Mahjoubeh J ; Purushothaman, Pravin ; Urbinati, Fabrizia ; Chen, Clarice ; Chou, Hsin-Jung ; Andreoletti, Gaia ; Bicciato, Silvio ; Grilli, Andrea

X-linked myotubular myopathy (XLMTM) is a severe congenital disease characterized by profound muscle weakness, respiratory failure, and early death. No approved therapy for XLMTM is currently available. Adeno-associated virus (AAV)-mediated gene replacement therapy has shown promise as an investigational therapeutic strategy. We aimed to characterize the transcriptomic changes in muscle biopsies of individuals with XLMTM who received resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) in the ASPIRO clinical trial and to identify potential biomarkers that correlate with therapeutic outcome. We leveraged RNA-sequencing data from the muscle biopsies of 15 study participants and applied differential expression analysis, gene co-expression analysis, and machine learning to characterize the transcriptomic changes at baseline (pre-dose) and at 24 and 48 weeks after resamirigene bilparvovec dosing. As expected, MTM1 expression levels were significantly increased after dosing (p < 0.0001). Differential expression analysis identified upregulated genes after dosing that were enriched in several pathways, including lipid metabolism and inflammatory response pathways, and downregulated genes were enriched in cell-cell adhesion and muscle development pathways. Genes involved in inflammatory and immune pathways were differentially expressed between participants exhibiting ventilator support reduction of either greater or less than 6 h/day after gene therapy compared to pre-dosing. Co-expression analysis identified similarly regulated genes, which were grouped into modules. Finally, the machine learning model identified five genes, including MTM1, as potential RNA biomarkers to monitor the progress of AAV gene replacement therapy. These findings further extend our understanding of AAV-mediated gene therapy in individuals with XLMTM at the transcriptomic level.

项与 Resamirigene Bilparvovec 相关的新闻（医药）

2025-07-21

·同写意

在迷雾中前行的AAV疗法

同写意年度巨献！！大会特设“基因治疗”分会，7月24-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！基因治疗是指通过向患者体内引入特定的细胞功能改变遗传物质来治疗遗传疾病的方法。实现方式包括体外或体内实施两种：体外基因治疗涉及提取患者的细胞，对其进行基因改造，然后重新注入患者体内；体内基因治疗则是直接将遗传物质递送到目标组织。基因治疗的关键在于将基因高效地递送到目标组织或细胞中，这一过程由称为载体的基因递送工具完成。载体分为病毒性和非病毒性两种，目前，共有43种基因治疗获批（图1），其中，17种采用病毒载体（包括AAV、腺病毒、逆转录病毒、慢病毒和单纯疱疹病毒），而26种采用非病毒载体（包括反义寡核苷酸、siRNA以及基于细胞的CRISPR基因编辑技术）。图1 获批的基因治疗产品和递送平台在in vivo基因治疗中，腺相关病毒（AAV）载体因其广泛的组织亲和性、相对良好的安全性以及多样的生产方式而受到开发者青睐，目前已有9款AAV基因治疗产品获批上市（表1）。表1 已获批AAV基因治疗产品TONACEA01AAV疗法基本原理腺相关病毒（Adeno-associated virus，AAV）是目前发现结构最简单的、无包膜的单链DNA病毒，由蛋白衣壳（capside）和长度为4.7kb的单链DNA基因组构成，衣壳长度为20 ~ 25nm，属于细小病毒家族。AAV自身不能复制，必须依赖于其它病毒复制，比如腺病毒、疱疹病毒、杆状病毒，有超过80%的人携带AAV，未发现AAV与任何疾病相关。病毒（Recombinant AAV，rAAV）是经工程改造的AAV载体，它剔除了AAV基因组全部编码蛋白Rep或Cap基因序列，只在两端保留作为包装信号的反式DNA序列（即ITR）。用于基因疗法载体的重组腺相关病毒（rAAV）携带的蛋白衣壳与野生型AAV几乎完全相同，然而基因组中编码病毒蛋白的部分完全被治疗性转基因（transgene）替代。AAV基因疗法应用策略主要有三类：1、基因置换：最常见的AAV介导的治疗干预是基因置换，其特点是引入功能基因副本治疗单基因疾病。该方法主要用于罕见和不可治疗的疾病，如莱伯氏先天性黑蒙症（一种遗传性视网膜疾病，Luxturna于2017年获得批准用于治疗该疾病）、小儿脊髓性肌萎缩症，（Zolgensma于2019年获得批准用于治疗该疾病）以及血友病A（凝血蛋白因子VIII缺乏引起，一种隐性x连锁疾病，Roctavian余2022年获得批准用于治疗该疾病）。2、基因添加：基因添加是AAV基因治疗应用最广泛的一种，因为它可以用于治疗较常见的非单基因复杂疾病，如慢性、自身免疫性或感染性疾病。使用AAV进行基因添加的例子包括正在进行的治疗类风湿性关节炎的临床试验。目前，Arthrogen正在进行1期临床试验(NCT02727764)。AAV载体携带IFN-β转基因，IFN-β是一种抗炎介质，在骨骼和软骨保护中发挥作用。3、基因沉默：与试图克服功能缺失突变的基因替换不同，基因沉默，也被称为RNA干扰(RNAi)，可以用来抑制有害的功能获得突变。在这种方法中，AAV转基因编码一个miRNA前体，该前体经靶细胞自身的RNAi机制加工产生miRNA，这是一个小的非编码RNA链，可以与mRNA对中的互补序列建立碱基，以抑制其表达。利用AAV进行基因沉默的大多数努力仍处于临床前研究阶段，因为沉默有几个必须解决的具体安全问题。一个主要问题是非目标沉默的可能性。另一个问题是RNAi饱和的机制。在这个机制中，转基因miRNA的表达可能压倒并破坏内源性miRNA的产生，导致细胞毒性。目前，unique已经开始了一项使用AAV基因疗法治疗亨廷顿舞蹈病的临床试验(NCT049493)，需要在核磁共振（MRI）成像的引导下，将该药物精准注射到大脑的壳核和尾状核区域。TONACEA02罕见病患者的救命稻草AAV疗法作为最先进的治疗方法之一，给无药可治的罕见病患者带来了新的希望。1AAV疗法与血友病2025年7月4日，NEJM发表了10例重度血友病B患者接受scAAV2/8-LP1-hFIXco单次快速输注治疗随访13年的结果（NCT00979238）：除短暂性肝转氨酶升高外，未观察到长期或新的AAV相关不良事件。因子IX表达保持稳定，十名参与者中有七名未服用因子IX预防药物。临床上，AAV基因转移使ABR和因子IX浓缩物用量减少了9倍以上，显著减轻了疾病负担。两名受试者出现了肿瘤病变，根据研究方案，这些病变被报告为可能与AAV相关的严重不良事件。然而，后续的分子研究和专家多学科评审表明，这些事件可能与AAV基因治疗无关，而是像之前描述的一样，归因于普通人群中普遍存在的年龄相关或环境风险因素。表2 10名患者基线及接受治疗后特征2AAV疗法与莱伯先天性黑蒙症莱伯先天性黑蒙症是一组遗传性视网膜疾病，会导致婴儿期视力严重下降。莱伯先天性黑蒙症的发病机制涉及20多个基因，这些基因最常参与光感受器纤毛运输、光传导、视觉周期和光感受器发育。首个针对遗传性视网膜疾病的基因疗法voretigene neparvovec-rzyl（Luxturna，Spark Therapeutics）于2017年获批，用于治疗由RPE65突变引起的莱伯先天性黑蒙。这种视网膜下基因疗法改善了功能性视力，并且大多数患者耐受性良好。从那时起，几种视网膜基因疗法一直在开发和临床试验中。ATSN-101是针对LCA1的基因疗法。2024年9月，Atsena发表了从ATSN-101的1/2期试验到治疗后12个月的所有患者的安全性和有效性数据：2019年9月12日至2022年5月5日期间，15名经基因确诊为LCA1的患者参与了本研究，所有患者均于2023年6月前完成了第12个月的随访。15名患者中，有13名（87%）接受了足量的300 μL视网膜下注射（包括高剂量组的所有9名患者）；队列1和2中各有一名患者的视网膜下注射量略有减少，分别约为200 μL和250 μL。对于高剂量组，合并后，治疗和未治疗的眼睛在白色和彩色刺激方面均存在显着差异。在第28天观察到高剂量治疗的眼睛相对于未治疗的眼睛有所改善，并且这种改善持续到第12个月；治疗的眼睛在第12个月改善了20.3 dB，而未治疗的眼睛仅改善了1.1dB。接受高剂量治疗的9名患者中，有6名在暗适应白色FST中表现出超过10 dB的改善，改善幅度高达46.5 dB。治疗12个月后，所有13名完成色觉刺激暗适应测试的患者均表现出视杆介导的反应，蓝色和红色敏感度之间约有2个对数单位的差异（21.7至28.7 dB）；除一名表现出视锥介导反应的患者外，所有患者的基线反应类似地都是视杆介导的。与暗适应FST相反，在光适应FST中没有观察到一致的改善；在11名完成色觉刺激光适应测试的患者中，只有两名在治疗12个月后表现出视锥介导的反应，而这些患者在基线时都有视锥介导的反应。3AAV疗法与常染色体隐性遗传性耳聋9型（DFNB9）OTOF基因突变是导致常染色体隐性遗传性耳聋9型（DFNB9）的核心病因，患者因内耳毛细胞突触囊泡功能缺陷而丧失听力。人工耳蜗是重度DFNB9患者的主要治疗方法，虽能部分恢复听觉，但存在音质失真、噪声环境识别困难等局限。OTOF基因疗法则直击疾病根源——通过腺相关病毒（AAV）载体将功能性OTOF基因精准递送至耳蜗内毛细胞，修复突触传递功能。2025年7月2日，《Nature Medicine》发表了中国研究团队在中国的五个医学中心对10名年龄在1.5-23.9岁之间的常染色体隐性遗传耳聋9型（DFNB9）患者进行的一项使用Anc80L65衣壳的AAV-OTOF基因治疗的单臂临床试验。临床试验的主要终点指标为5年内的安全性和耐受性，次要终点指标评估听觉功能。对10名随访了6-12个月的患者（其中包括1名接受了两次注射治疗的患者）的初步研究结果表明，该AAV-OTOF基因疗法耐受性和安全性良好，共出现162起1/2级不良事件，中性粒细胞百分比降低是最常见的不良事件（在162例中有16例）。所有10名患者均接受了至少6个月的随访，他们的平均纯音听阈从基线的106分贝改善至52分贝（正常谈话时的音量水平）。其他次要终点指标也显示出类似改善，包括平均点击声听觉脑干反应（ABR）阈值、短纯音ABR阈值和听觉稳态反应（分别从101分贝改善至48分贝、91分贝改善至57分贝、80分贝改善至64分贝）。TONACEA03肝毒性阴影笼罩AAV的肝毒性引起的患者死亡事件时见公布，引起监管警惕与业内担忧：• 2025年3月，Sarepta公司报告称，一名16岁患者在接受其已获批上市的杜氏肌营养不良症基因疗法Elevidys治疗后发生了严重急性肝损伤并最终导致死亡。2025年6月15日，Sarepta再度发布公告，表示Elevidys出现第二例由ALF导致的死亡病例。而后FDA发布的公告中明确指出，目前已确定两例死亡病例均与Elevidys治疗存在关联，患者均在接受治疗后两个月内出现转氨酶升高并住院，最终进展为ALF而死亡。之后将进一步评估Elevidys引发ALF（导致住院或死亡等严重后果）的风险，并考虑是否需采取进一步监管措施（如更新黑框警告、限制使用人群或撤市）。• 2022年，诺华（Novartis）报告了两名患儿在接受用于治疗脊髓性肌萎缩症的Zolgensma治疗后，因急性肝功能衰竭而发生的死亡。• 2020年至2021年间，安斯泰来研发的用于治疗X连锁肌管病（XLMTM）的AAV8基因疗法AT132，在其ASPIRO临床研究（NCTO3199469）的高剂量组（3 x 10^14 vg/kg）中，先后导致4名患儿因严重的免疫介导肝损伤、肝功能衰竭及继发性脓毒症死亡。而后该项目彻底终止。TONACEA04明暗难辨的前路聚焦罕见病事实上对AAV疗法的开发者来说是把双刃剑，一方面，罕见病背后的各种快速注册制度允许开发者通过少量患者的临床数据实现快速上市，另一方面，狭窄的受众人群，给商业化带来了难以逾越的障碍，即使强大如pfizer也不得不壮士断腕。• 2025年3月，罗氏对Spark启动“根本性重组”，计提24亿美元商誉减值，裁撤337个岗位并将剩余310名员工并入母公司，Spark首款获批基因疗法产品Luxturna（治疗遗传性视网膜疾病疗法）2023年销售额暴跌59%，从2022年的5000万美元暴跌至约2000万美元。罗氏直言Spark的未来收入与协同效应无法覆盖账面价值，因此采取重组。• 2025年2月27日，Vertex（福泰制药）终止与Verve Therapeutics价值4.66亿美元的肝病基因编辑合作，收回2022年以来投入的2500万美元首付款及3500万美元股权投资。• 2025年，辉瑞（Pfizer）因零患者使用宣布Beqvez撤市，清空了基因疗法的商业和临床管线，此前，其DMD基因疗法fordadistrogene movaparvovecIII期临床失败，与Sangamo合作的A型血友病项目giroctocogene fitelparvovec亦于2024年末终止。• 2023年武田制药（Takeda）宣布结束早期的AAV项目，相关项目成员成立了Crosswalk，并收购了相关产品但与此同时，依然有玩家看好AAV的前景，尤其是在CNS领域的潜力，因此衍生的BD交易也并不鲜见。2025年Sangamo与礼来达成协议，将获得Sangamo专有的嗜神经性（neurotropic）腺相关病毒（AAV）衣壳STAC-BBB在一个初始疾病靶点上的全球独家使用权，还可以增加最多四个神经系统疾病靶点，以开发针对中枢神经系统（CNS）特定疾病的基因疗法。Sangamo将从礼来获得1800万美元的预付款，并将在五个潜在的靶点上获得高达14亿美元的额外靶点费和里程碑付款，以及潜在净销售额的分层特许权使用费。表3 AAV疗法的BD交易— 结语 —AAV疗法作为基因疗法的成功范本给许多无药可治的罕见病患者带来了康复的希望，但不断出现的肝毒性事件却为此笼罩上了一层阴影，与此同时，艰难的商业化环境进一步恶化了基因疗法biotech的生存环境，让AAV的未来显得明暗难辨，但也请期待新的改造技术的出现，实现疗效、安全性与商业化的三赢。参考文献：（上下滑动查看更多）1.Wang H, Chen Y, Lv J, Cheng X, Cao Q, Wang D, Zhang L, Zhu B, Shen M, Xu C, Xun M, Wang Z, Tang H, Hu S, Cui C, Jiang L, Yin Y, Guo L, Zhou Y, Han L, Gao Z, Zhang J, Yu S, Gao K, Wang J, Chen B, Wang W, Chen ZY, Li H, Shu Y. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nat Med. 2024 Jul;30(7):1898-1904. doi: 10.1038/s41591-024-03023-5. Epub 2024 Jun 5. PMID: 38839897; PMCID: PMC11271389.2.Reiss UM, Davidoff AM, Tuddenham EGD, Chowdary P, McIntosh J, Muczynski V, Journou M, Simini G, Ireland L, Mohamed S, Riddell A, Pie AJ, Hall A, Quaglia A, Mangles S, Mahlangu J, Haley K, Recht M, Shen YM, Halka KG, Fortner G, Morton CL, Gu Z, Hayden RT, Neufeld EJ, Okhomina VI, Kang G, Nathwani AC. Sustained Clinical Benefit of AAV Gene Therapy in Severe Hemophilia B. N Engl J Med. 2025 Jun 12;392(22):2226-2234. doi: 10.1056/NEJMoa2414783. PMID: 40499172; PMCID: PMC7617823.3.Yang P, Pardon LP, Ho AC, Lauer AK, Yoon D, Boye SE, Boye SL, Roman AJ, Wu V, Garafalo AV, Sumaroka A, Swider M, Viarbitskaya I, Aleman TS, Pennesi ME, Kay CN, Fujita KP, Cideciyan AV. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study. Lancet. 2024 Sep 7;404(10456):962-970. doi: 10.1016/S0140-6736(24)01447-8. PMID: 39244273.4.Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019 May;18(5):358-378. doi: 10.1038/s41573-019-0012-9. PMID: 30710128; PMCID: PMC6927556.5.Bulcha JT, Wang Y, Ma H, Tai PWL, Gao G. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther. 2021 Feb 8;6(1):53. doi: 10.1038/s41392-021-00487-6. PMID: 33558455; PMCID: PMC7868676.

基因疗法临床研究siRNA寡核苷酸上市批准

2025-04-01

·CPHI制药在线

天价基因疗法“塌房”，AAV还是理想载体吗？

关注并星标CPHI制药在线近日，SareptaTherapeutics宣布，其治疗杜氏肌营养不良症（DMD）的基因疗法Elevidys出现首例治疗相关死亡病例，该患者在接受Elevidys治疗后因急性肝衰竭（ALF）死亡。受此消息影响，公司当日股价暴跌27%，目前总市值约71亿美元。Elevidys是一款基于腺相关病毒载体（AAVrh74）的重组基因疗法。此次患者死亡事件，使基因疗法的安全性再次被推上风口浪尖，尤其是AAV载体，还是基因疗法的理想载体吗?关于DMD首款基因疗法DMD是一种致命的罕见X连锁退行性神经肌肉疾病，全世界大约每3500-5000名男性新生儿中就有1名DMD患儿。DMD主要是由体内编码抗肌萎缩蛋白（dystrophin）的基因发生突变引起，这种致病性变异会导致肌纤维的完整性遭到破坏，进而导致肌肉纤维化以及肌肉的萎缩与退化。由此常引发呼吸和/或心脏衰竭，使得患者的预期寿命很少超过40岁。很长时间以来，DMD治疗策略主要以缓解症状和改善生活质量为主，没有治愈的方法。随着基因疗法的进展，旨在恢复抗肌萎缩蛋白正常表达的基因治疗手段为DMD患者带来了治愈希望。Elevidys由Sarepta和罗氏联合开发，是一种基于腺病毒（AAVrh74）的重组基因疗法，于2023年6月获FDA批准上市，成为全球首款针对DMD的基因疗法，价格设定为每剂310万美元。虽然价格高昂，但Elevidys的业绩依然亮眼。2024年第四季度，Elevidys总营收达3.842亿美元，环比增长112%。结合其2024年前三个季度的业绩，Elevidys在2024年全年总营收为8.21亿美元，远超公司预期。Sarepta预计，2025年Elevidys产品收入将在29亿至31亿美元之间。虽然业绩可观，但安全性问题犹如悬顶的达摩克利斯之剑。从作用机制上来说，Elevidys是将表达微抗肌萎缩蛋白的转基因包装在AAV病毒载体中，而AAV载体在体内自然分布倾向于肝脏，即便Elevidys为了降低中枢神经系统暴露风险，采用了从非人灵长类动物中分离出的AAVrh74病毒载体进行递送，但仍然避免不了肝毒性风险。作为基因疗法成败的关键，AAV还是理想载体吗？AAV是一种单链DNA病毒，本身无自主复制能力。一般情况下，AAV载体基因组几乎不整合到宿主细胞基因组中，而是以附加体的形式游离于宿主染色体之外，因此，在非分裂组织细胞中能够长时间表达目的基因。AAV载体还具有较高的转导效率、且宿主范围广，可转导分裂和静止期细胞，具有特定组织和细胞的靶向性、相对较低的免疫原性等。因此，在众多病毒载体中，AAV载体凭借着较高的安全性与转基因效率，成为了基因治疗领域中的一款明星载体，约90%的基因治疗临床试验都在使用AAV。尽管如此，AAV还是不可避免地要面对肝毒性风险。早在2020年，安斯泰来旗下一款基因疗法AT132，因患者发生肝功能衰竭，试验一度暂停。AT132是一款由AAV8载体装载MTM1基因的功能性拷贝，用于X连锁肌管性肌病（XLMTM）的治疗。无独有偶，辉瑞公司的在研DMD基因疗法PF-06939926曾在II期临床研究中出现了患者死亡病例，且III期CIFFREO研究未达主要终点，最终被终止研发。除了肝毒性风险外，AAV载体是否致癌的猜测也存在争议。虽然在进入细胞之后，AAV携带的转基因通常不会整合到细胞的基因组中。但是在小鼠模型中，研究人员发现，少量AAV载体的基因组会整合到宿主的DNA中，甚至是整合到包含多个调节RNA的Rian位点（与肝细胞癌发病相关）。在2020年，UniQure的一款针对血友病的AAV基因疗法使得一名患者患上肝细胞癌（HCC），这位患者于2019年末接受了递送IX基因的AAV5载体的注射。尽管后面证实该患者患有乙肝和丙肝病毒感染，本身是HCC的高发人群，因此发现的肿瘤或与AAV治疗无关。但关于AAV载体致癌的争议从未停止。2021年，FDA曾就AAV基因疗法的毒性风险召开了为期两天的咨询委员会会议，集中讨论了AAV载体插入的致癌风险、临床前研究或临床研究中提示的肝毒性、神经毒性风险等问题。除了安全性问题外，AAV载体也存在一些其他缺陷，比如包装容量不高于5K，这限制了AAV载体在不同疾病治疗方面的更广泛应用。不少患者对AAV有预存免疫反应，这进一步限制了AAV载体在患者人群中的更广泛应用。不可否认，AAV载体目前依然是基因疗法应用最广泛的载体。Elevidys强劲的市场表现也说明了对于致死性疾病，患者群体愿意承担可控风险以换取生存希望。但这不应该成为基因疗法安全性问题的避风港。对新一代AAV载体的改进，应当瞄准提升疗效，对目标细胞和器官的生物选择性更高这个方向。参考资料:1.https://www-nature-com.libproxy1.nus.edu.sg/articles/s41392-021-00487-62.https://www.uniqure.com/investors-media/press-releases　3.https://whtc.com/2022/08/11/novartis-reports-zolgensma-caused-two-deaths-from-liver-failure/END2025金笔奖征文活动开启，来投稿吧！领取CPHI & PMEC China 2025展会门票智药研习社直播预告来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

基因疗法上市批准

2025-02-13

·药智网

日本制药巨头狂砍管线

跨国药企战略调整进行时。安斯泰来（Astellas）正在重新调整其研发管线，将重点放在后期机会上，并终止一些早期研究项目。而在不久前，安斯泰来对公司高层职位进行重大调整，其中包括首席科学官Yoshitsugu Shitaka博士和首席制造官Hideki Shima的离职，并将现任首席医学官Tadaaki Taniguchi博士升任为新设立的首席研发官职位。 1 砍管线、调结构安斯泰来制药集团（Astellas Pharma Inc.）是一家总部位于日本东京的跨国制药企业，成立于2005年，由原日本山之内制药株式会社与藤泽制药株式会社合并而成。公司不仅拥有前列腺癌神药安可坦（Xtandi）这一重磅新药，还在新晋热门的抗体药物偶联物（ADC）领域大获成功，其Padcev获批与默沙东的Keytruda联合用于一线治疗膀胱癌。然而，在研发回报率持续走低的大环境下，安斯泰来也开始战略转向，聚焦更易成功的领域。据悉，安斯泰来公司正在进行一项为期四年的成本削减计划，旨在到2027财年结束时（届时与辉瑞合作的前列腺癌药物Xtandi预计将在美国失去市场独占权）实现1200亿至1500亿日元（8亿至10亿美元）的年度成本节约。根据Fierce Pharma消息，安斯泰来将终止多个早期项目，优先推进20+后期管线。同时，安斯泰来对公司高层职位进行重大调整，其中包括首席科学官和首席制造官的离职，并将现任首席医学官Tadaaki Taniguchi博士升任为新设立的首席研发官职位。 2 聚焦后期项目近年来，安斯泰来在新型技术上投入了大量资金。 2019年，安斯泰来通过连续收购Audentes Therapeutics和Xyphos Biosciences在细胞和基因治疗方面进行了大量投资。去年，公司还与慢病毒载体递送专家Kelonia Therapeutics、同种异体CAR-T生物技术公司Poseida Therapeutics（最近被罗氏收购）和基因组医学专家Sangamo Therapeutics建立了合作关系。目前，安斯泰来多个项目已接近概念验证阶段的结果读出，但公司对开发进度仍不满意。而且，安斯泰来巨额收购的基因疗法AT132，在临床试验中导致四名患者死亡。在遭遇了一些挫折以及大型制药公司在CGT行业的普遍撤资后，安斯泰来也失去了耐心。安斯泰来首席战略官Adam Pearson表示，公司将把更多重点转向后期机会，将更多精力投入到风险较低的治疗方式上。 “我们将把投资转向更多较为成熟的治疗方式，如双特异性抗体、免疫刺激性抗体偶联药物（ADCs）、蛋白降解疗法等”Pearson说。此前，安斯泰来已与辉瑞合作开发了明星ADC药物Padcev，该药在膀胱癌治疗中取得了突破性成功。Pearson表示，如果有“合适的、处于后期阶段的、适合引进许可的机会”，公司可能会引进更多ADC项目。此外，安斯泰来还关注神经肌肉疾病、免疫肿瘤学、失明与再生以及靶向蛋白降解疗法，在这些领域或将进行更多收购或引进管线。 3 结语安斯泰来的战略转向并非孤例。在研发回报率持续走低、政策监管趋严的行业背景下，诺华、赛诺菲等巨头近期也纷纷调整管线，“更有效地将资源分配给最有前途的项目”，以期在日益激烈的市场竞争中保持竞争力。参考来源： 1.https://www.fiercepharma.com/pharma/astellas-shifts-investment-focus-later-stage-opportunities-amid-reprioritization 2.稳稳队：又一家日本药企，大变动声明：本内容仅用作医药行业信息传播，不代表药智网立场。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 小月石合作、投稿 | 马老师 18323856316（同微信）阅读原文，是受欢迎的文章哦

抗体药物偶联物免疫疗法并购细胞疗法基因疗法

100 项与 Resamirigene Bilparvovec 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15121

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
先天性肌病	临床3期	美国	Astellas Gene Therapies, Inc.	2017-08-02
先天性肌病	临床3期	加拿大	Astellas Gene Therapies, Inc.	2017-08-02
先天性肌病	临床3期	法国	Astellas Gene Therapies, Inc.	2017-08-02
先天性肌病	临床3期	德国	Astellas Gene Therapies, Inc.	2017-08-02
类风湿关节炎	临床1期	中国	珠海市丽珠单抗生物技术有限公司	2014-07-08

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03199469 (ASPIRO, Lancet Neurol \| Pubmed) 人工标引	临床1/2期	先天性肌病	26	AT132 higher dose	憲鑰齋範積選窪鹽簾網(淵鹹築膚繭廠範願憲網) = 壓壓醖膚顧醖選遞膚製範壓夢壓繭鹽齋選構繭 (積簾簾襯製廠衊鹹醖繭, -6.15 ~ -39.37) 更多	积极	2023-11-16
				AT132 lower dose	憲鑰齋範積選窪鹽簾網(淵鹹築膚繭廠範願憲網) = 廠鹹觸製齋積廠夢鬱窪範壓夢壓繭鹽齋選構繭 (積簾簾襯製廠衊鹹醖繭, -40.22 ~ -115.24) 更多
NCT03199469 (Aspiro, Biospace) 人工标引	N/A	先天性肌病	24	AT132 (high-dose)	鹹顧壓構選衊獵膚觸鹽(壓衊餘獵獵選積窪選築) = 願齋獵積淵鹽繭繭廠鬱廠糧糧鹽壓膚網構鏇鏇 (窪衊衊築鹽築獵襯醖蓋 ) 更多	不佳	2023-11-16
				AT132 (lower dose)	鹹顧壓構選衊獵膚觸鹽(壓衊餘獵獵選積窪選築) = 築範夢艱膚顧鬱鏇憲遞廠糧糧鹽壓膚網構鏇鏇 (窪衊衊築鹽築獵襯醖蓋 ) 更多
NCT03199469 (ASPIRO, PRNewswire) 人工标引	临床2/3期	先天性肌病	24	AT132 1.3 x 1014 vg/kg	齋廠夢醖遞壓獵鬱觸築(選範鏇選窪廠鑰選壓構) = 顧觸範餘積網鑰觸夢餘餘鹹築遞鹹壓憲鏇糧繭 (繭憲憲構顧顧餘鹹鹹夢 ) 更多	积极	2023-11-15
				AT132 3.5 x 1014 vg/kg	齋廠夢醖遞壓獵鬱觸築(選範鏇選窪廠鑰選壓構) = 製壓艱簾蓋鹹艱範壓網餘鹹築遞鹹壓憲鏇糧繭 (繭憲憲構顧顧餘鹹鹹夢 ) 更多
ATS2022	N/A	先天性肌病	-	AT132 lower-dose (1.3 x 10^14 vg/kg)	窪願鏇襯簾醖淵構憲鹹(繭襯範遞膚築願齋遞鹹) = As of January 2021, three deaths in the higher-dose cohort (attributed to severe liver dysfunction) and three deaths in the control cohort (2/3 attributed to respiratory events) occurred. As of September 2021, a newly dosed participant in the lower-dose cohort has died; the cause of death is still pending. 衊鹽鹽積簾獵製獵獵遞 (壓鹽觸壓選醖蓋構簾鏇 )	-	2022-05-15
				AT132 higher-dose (3.5 x 10^14 vg/kg)