A Long-term Safety Study in Brazilian Patients With a Confirmed Diagnosis of Spinal Muscular Atrophy (SMA) Treated With Onasemnogene Abeparvovec (Zolgensma®) - ARISER Study

A long-term safety study in Brazilian patients with a confirmed diagnosis of Spinal Muscular Atrophy (SMA) treated with Onasemnogene Abeparvovec (Zolgensma®)

开始日期2023-11-22

申办/合作机构

Novartis Pharmaceuticals Corp.

IRCT20221024056284N1 / CompletedN/AIIT

Evaluation the color match of two single shade resin composites; Charisma Diamond ONE and Charisma Topaz ONE in class five restorations and assessment of dentist and patient satisfaction

开始日期2023-01-21

申办/合作机构

Mashhad University of Medical Sciences

100 项与 Onasemnogene abeparvovec 相关的临床结果

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100 项与 Onasemnogene abeparvovec 相关的转化医学

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100 项与 Onasemnogene abeparvovec 相关的专利（医药）

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303

项与 Onasemnogene abeparvovec 相关的文献（医药）

2024-12-01·Lancet Regional Health-Europe

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Article

Background:

Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH).

Methods:

This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status.

Findings:

343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups.

Interpretation:

Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio.

Funding:

The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

2024-12-01·MUSCLE & NERVE

Outcomes of early‐treated infants with spinal muscular atrophy: A multicenter, retrospective cohort study

Article

作者: Hamid, Omer Abdul ; Lee, Bo Hoon ; Herbert, Karen ; Farah, Hiba ; King, Kiana ; Kuntz, Nancy L. ; Zaidman, Craig M. ; Fisher, Mark ; Gibbons, Melissa ; Parsons, Julie ; Lakhotia, Arpita ; Rehborg, Rebecca ; Rogers, Amanda ; Goedeker, Natalie L. ; Kichula, Elizabeth ; Harmelink, Matthew ; Brandsema, John F. ; Veerapaniyan, Aravindhan ; Felker, Marcia V. ; Arya, Kapil ; Farrar, Michelle A.

Abstract:

Introduction/Aims:

While prompt identification and treatment of infants with spinal muscular atrophy (SMA) can ameliorate outcomes, variability persists. This study assessed management and outcomes of early‐treated infants with SMA.

Methods:

We analyzed retrospective data at 12 centers on infants with SMA treated at age ≤6 weeks from August 2018 to December 2023.

Results:

Sixty‐six patients, 35 with two SMN2 copies and 31 with ≥3 SMN2 copies, were included. Twenty‐five (38%, 22 with two SMN2 copies), had SMA findings before initial treatment which was onasemnogene abeparvovec in 47 (71%) and nusinersen in 19 (29%). Thirty‐two received sequential or combination treatments, including 16 adding nusinersen or risdiplam due to SMA findings following onasemnogene abeparvovec. All sat independently. Compared to children with ≥3 SMN2 copies, those with two SMN2 copies were less likely to walk (23/34 [68%] vs. 31/31 [100%], p < .001) and less likely to walk on time (9/34 [26%] vs. 29/31 [94%], p < .001); one non‐ambulatory child was <18 months old and was excluded from this analysis. No patients required permanent ventilation or exclusively enteral nutrition; six required nocturnal non‐invasive ventilation and four utilized supplemental enteral nutrition, all with two SMN2 copies.

Discussion:

Early treatment of infants with SMA can improve outcomes as indicated by our cohort, all of whom sat independently and are without permanent ventilation. However, our study demonstrates ongoing disability in most children with two SMN2 copies despite early monotherapy and emphasizes the need for additional research, including earlier monotherapy, initial combination therapy, prenatal treatment, and non‐SMN modifying treatments.

2024-11-01·MUSCLE & NERVE

Nutrition outcomes of disease modifying therapies in spinal muscular atrophy: A systematic review

Review

作者: O'Brien, Katie ; Woodcock, Ian R. ; Nguo, Kay ; Yiu, Eppie M. ; Billich, Natassja ; Davidson, Zoe E.

Abstract:

The nutritional implications of spinal muscular atrophy (SMA) are profound. Disease modifying therapies (DMT) have improved clinical outcomes. This review describes the impact of DMT on nutrition outcomes. A systematic search strategy was applied across seven databases until May 2023. Eligible studies measured nutrition outcomes in individuals with SMA on DMT (nusinersen, risdiplam or onasemnogene abeparvovec [OA]) compared to untreated comparators. Nutrition outcomes included anthropometry, feeding route, swallowing dysfunction, dietary intake, dietetic intervention, nutritional biochemistry, metabolism, gastrointestinal issues and energy expenditure. Articles retrieved were screened in duplicate, data were extracted and appraised systematically. Sixty three articles from 54 studies were included; 41% (n = 22) investigated nusinersen in pediatric participants with SMA type 1. Anthropometry (n = 18), feeding route (n = 39), and swallowing dysfunction (n = 18) were the most commonly reported outcomes. In combined pediatric and adult cohorts, BMI z‐score remained stable post nusinersen therapy. The proportion of children with SMA requiring enteral nutrition was stable post nusinersen therapy. Ability to thrive at age 1.5 years was higher in children treated in early infancy with OA compared to historical controls. Significant heterogeneity existed across study population characteristics and outcome measures. Nusinersen may prevent deterioration in some nutrition outcomes; and OA in early infancy may be associated with improved nutrition outcomes. Timing of DMT initiation is an important consideration for future nutrition research. Studies investigating nutrition as a primary outcome of DMT, using consistent outcome measures are required for nutritional management strategies for this cohort to be appropriately tailored.

547

项与 Onasemnogene abeparvovec 相关的新闻（医药）

2024-11-18

·GlobeNewswire-Health Care

Trogenix Unveils Revolutionary Platform to Transform Cancer Treatment Through Precision Viral Immunotherapy

Trogenix Unveils Revolutionary Platform to Transform Cancer Treatment Through Precision Viral Immunotherapy Company founded by 4BIO Capital and Professor Steve Pollard as a spinout from the University of Edinburgh to commercialise its breakthrough Synthetic Super-Enhancer platform, Odysseus, to enable unprecedented precision in targeting aggressive cancersIQ Capital, Cancer Research Horizons, National Brain Tumor Society, AIN Ventures and Old College Capital now also investors in Trogenix Dr Ken Macnamara, a veteran gene therapy executive who held leadership roles at Bayer/AskBio and Synpromics, appointed as Chief Executive OfficerTay Salimullah, former executive team member at Novartis Gene Therapies, joins the Board as Trogenix advances towards clinical development Edinburgh, UK, 18 November 2024 -- Trogenix Ltd today emerged from stealth mode to unveil its groundbreaking therapeutic platform for treating aggressive cancers. Built from inception by 4BIO Capital, which specialises in creating breakthrough therapeutic companies, Trogenix spun out from the University of Edinburgh in 2023 and raised a seed financing round earlier this year. Leading life science and deep tech investors IQ Capital, Cancer Research Horizons, the US National Brain Tumor Society’s Brain Tumor Investment Fund, AIN Ventures and the University of Edinburgh’s venture investment fund, Old College Capital, have also invested in Trogenix. "Cancer remains a leading cause of death worldwide, with current therapies often falling short, especially for aggressive solid tumours," said Dr Ken Macnamara, Chief Executive Officer of Trogenix. "We founded Trogenix to transform cancer treatment from chronic disease management to potentially curative one-time treatments. Our Synthetic Super-Enhancer technology represents a significant breakthrough in precision cancer therapy, offering unprecedented selectivity in targeting cancer cells and activating the body's own immune system against tumours, all while leaving healthy cells untouched." The company's lead programme targets glioblastoma (GBM), the most aggressive form of brain cancer, where only 25% of patients survive beyond one year. Preclinical studies have demonstrated curative responses with no toxicity and evidence of persistent anti-tumour immunity, with Phase 1/2 clinical trials planned for 2025. "Trogenix exemplifies our approach to advancing revolutionary therapeutic platforms from concept to reality," said Dmitry (Dima) Kuzmin, Managing Partner at 4BIO Capital and Founding Chairman of Trogenix. "By combining our deep expertise in advanced therapies with the company's breakthrough science, we've helped shape a platform with the potential to fundamentally change cancer treatment. The convergence of synthetic biology, machine learning, gene therapy, and precision targeting in Trogenix's technology represents exactly the kind of innovation needed to deliver next-generation curative treatments. Being able to discern a cancer cell in situ from a healthy cell without relying on a surface antigen is truly revolutionary." The company's proprietary Synthetic Super-Enhancers (SSEs) are engineered DNA elements that act as docking stations for transcription factors uniquely expressed in aggressive cancer cells. This enables highly selective and potent gene control with multiple layers of safety, including direct tumour injection for localised delivery and self-limiting control mechanisms. Through these SSEs, Trogenix's Odysseus platform delivers a comprehensive attack on cancer through controlled cell killing via targeted expression of cytotoxic payloads, immune modulation to overcome tumour-induced immunosuppression, and a unique ‘Trojan Horse’ approach that reawakens the immune system to provide long-term protection against recurrence. World-Class Leadership Team Trogenix emerged from groundbreaking research at the University of Edinburgh - including its UK Centre for Mammalian Synthetic Biology and Institute for Regeneration and Repair - and the Cancer Research UK Scotland Centre. The company was co-founded by Professor Steve Pollard, a renowned authority in regenerative medicine and cancer biology, who serves as Chief Scientific Officer. Under his leadership, the company has rapidly advanced its revolutionary SSE platform from concept to preclinical proof-of-concept. Chief Executive Officer Dr Ken Macnamara brings extensive leadership experience in gene therapy and biotech, including senior roles at AskBio (a Bayer company), and involvement in three successful M&A exits. "Our Odysseus platform represents a significant advancement in cancer treatment," said Professor Steve Pollard, Chief Scientific Officer of Trogenix. "By precisely targeting cancer cell states rather than just cell types, we can achieve unprecedented selectivity while activating the body's own immune system against the tumour. Our preclinical studies in glioblastoma have demonstrated complete responses with no toxicity and evidence of persistent anti-tumour immunity." Beyond GBM, Trogenix is advancing programmes in colorectal cancer liver metastases, hepatocellular carcinoma, lung squamous cell carcinoma, and regenerative medicine, with the goal of submitting five Investigational New Drug (IND) applications in five years. Strategic Board Appointment As Trogenix advances its groundbreaking platform toward clinical development, the company has appointed Tay Salimullah to its Board of Directors, his first Board appointment since leaving Novartis Gene Therapies. Tay has over 20 years of leadership experience in the rare disease and MedTech sectors, with a proven track record in incubating and scaling innovative, high-value technologies, including cell and gene therapies. He spent over a decade at Novartis in a series of leadership roles. As an Executive team member at Novartis Gene Therapies, Tay executed a new commercial model for Zolgensma® securing approvals in more than 55 countries, helping to treat over 4,000 patients, and generating more than $5 billion in revenue. Prior to his roles at Novartis, Tay worked in a variety of investment and healthcare roles, including a decade at Pfizer where he held several strategic and commercial roles. His expertise spans drug development, pricing science, market access, and operational excellence in high-value healthcare solutions. Tay holds a BSc in Management Sciences from the University of Brunel, London. About Trogenix Trogenix unites cutting-edge technologies in genomics, oncology, immunotherapy, and gene therapy to create a revolutionary therapeutic approach through its Odysseus platform. Using proven AAV vectors, our proprietary Synthetic Super-Enhancers (SSEs) are delivered directly to tumour cells without detection. Our SSEs enable unprecedented precision in gene control, effectively revealing cancer to the body's immune system and killing tumour cells. For any cells escaping Trogenix's technology, our 'Trojan horse' reawakens the immune system, countering recurrence and offering potentially curative 'one-and-done' treatments for aggressive tumours. With our lead asset showing curative potential in preclinical glioblastoma studies, we're poised to transform treatment paradigms across multiple cancer types and explore applications beyond oncology, such as regenerative medicine. For more information, visit www.trogenixbio.com. About 4BIO Capital 4BIO Capital (‘4BIO’) is an international venture capital firm headquartered in London, focused solely on the advanced and emerging therapies sector. The 4BIO team, which has an unrivalled network within the advanced therapy sector, comprises leading advanced therapy scientists and experienced life science investors. The firm maintains a global footprint across the US, Europe and Asia with an objective to create, invest in, support, and grow early-stage companies. Its ultimate goal is ensuring access to potentially curative therapies for all patients, with a specific focus on viable, high-quality opportunities in cell and gene therapy, RNA-based therapy, targeted therapies, and the microbiome. 4BIO is currently investing out of its Fund III, having secured support from prominent global institutional investors, including the Children’s Minnesota, UPMC, Development Bank of Japan, Kyowa Kirin, Exor, and many other endowments and foundations. For more information, please visit www.4BioCapital.com For more media enquiries, please contact: trogenix@icrhealthcare.com

高管变更基因疗法免疫疗法

2024-11-13

·派真生物PackGene

IF=40.5，跟着高分综述深入学习基因治疗递送载体AAV-免疫原性和应对策略篇

近期Signal Transduction and Targeted Therapy杂志（IF=40.5）上发表了一篇重量级AAV基因治疗综述文章（通讯作者为美国马萨诸塞大学Chan医学院的高光坪教授），深入探讨了AAV基因治疗的最新突破与未来趋势。这篇文章不仅汇聚了行业内的权威观点，更揭示了关键技术的最新动态，为学术界和产业界的创新提供了全新启发。前几章我们分别学习了AAV的基础知识、AAV的载体开发、AAV的生产工艺以及AAV的临床应用，相信大家都有不少收获，下面我们继续深入学习AAV临床应用中存在的免疫原性和应对策略。 rAAV基因治疗临床应用的挑战和局限性 rAAV衣壳的性能与给药方式密切相关，因此需要探索不同的递送方式，以便将其递送至合适的位置。每种递送方式和衣壳的选择都应根据具体的疾病、靶向区域、器官系统，以及患者年龄等因素来确定（表2）。表2 rAAV不同给药方式的优点和缺点一个经典的例子是血脑屏障（BBB）的存在，它有效地保护了中枢神经系统，也成为基因治疗需要克服的一个重要障碍。一些rAAV衣壳能够有效穿过血脑屏障。如果治疗的目标仅限于大脑的某个小区域，那么通过静脉注射给药以靶向中枢神经系统就不是最优选择，因为它需要的载体剂量较大，且可能导致较大的副作用，同时无法实现对目标区域的最佳转导。在这种情况下，直接且局部的递送方式至关重要，AADC的治疗案例便是一个典型的例子。然而，即使是在有限的区域内递送，衣壳的选择也必须非常谨慎。比如，rAAV9即便在局部递送时也表现出明显的组织扩散和较广泛的亲和性，而像rAAV2这样的血清型则转导能力较为有限。另一个挑战是从临床前研究到临床试验的转化。为了降低静脉注射所需的高剂量带来的载体成本和风险，通常采用脑脊液空间给药来实现中枢神经系统的广泛转导。然而，将小鼠、大鼠甚至更大动物的研究结果外推到人类身上面临巨大的挑战。例如，rAAV9在小鼠中能够实现全脑转导，因为小鼠的侧脑室和皮层之间的距离仅为几毫米，而在人类中，这个距离则是几厘米。因此，采用脑脊液递送方式进行广泛的中枢神经系统转导的临床试验，必须证明这种递送方式在人类中的可转化性。 rAAV的免疫原性除了物理屏障之外，rAAV还面临着免疫系统设立的多重生物屏障，这些包括预存免疫、补体激活、天然免疫模式和危险信号受体，以及适应性免疫中的B细胞和T细胞反应（图6）。在这里，我们将讨论每种免疫屏障如何对载体转导产生负面影响，以及现有的潜在解决方案。图6 rAAV基因治疗中的免疫反应。a. 预先存在的AAV特异性抗体可能与rAAV相互作用，阻止其进入目标细胞。来自细菌的内肽酶IdeS及其同源物能够将抗体切割成Fab和Fc片段，从而缩短抗体在血液中的半衰期，并消除Fc介导的功能。另外，也可以通过修饰rAAV衣壳或将其包装在外泌体（EVs）中，以防止被抗体的识别。b. 在给予高剂量rAAV时，观察到补体激活现象，其具体机制尚不清楚。主要假设是rAAV与细胞表面结合，通过与补体C1q的相互作用激活经典途径，导致C4和C2裂解形成C3转化酶C4b2b。随后，C3被裂解并形成C5转化酶，裂解C5成C5b，C5b与C6-9结合形成膜攻击复合物（MAC），直接导致细胞裂解，从而引发肝脏或肾脏损伤。补体激活还可能引发内皮损伤、血栓性微血管病（TMA）和非典型溶血性尿毒症综合征（aHUS）。环肽APL-9是C1抑制剂，依库珠单抗则可抑制C1、C3和C5，可能有助于抑制补体激活级联反应。c. 包括TLR2（识别病毒衣壳）、TLR9（识别未甲基化CpG）和RIG-I/MDA5（识别双链RNA）在内的天然免疫受体已被证实能够促进炎症反应。通过一系列信号转导事件，IRF3、IRF7和NF-κB会被磷酸化并转移到细胞核，激活I型干扰素（IFN I）、干扰素刺激基因（ISGs）和促炎细胞因子，进而介导抗病毒免疫和炎症反应。许多信号通路的组成成分可以被药物抑制剂靶向。此外，来自端粒的io2序列（一种哺乳动物端粒来源的ODN TTAGGG重复序列）能够抑制TLR9的激活。d. GOI的表达产物和衣壳可以通过蛋白酶体加工为肽段，随后由MHC-I或MHC-II分子进行呈递。识别这些肽段的CD8和CD4 T细胞将被激活。CD8 T细胞可能会直接杀死rAAV转导的细胞，而CD4 T细胞则可以协助CD8 T细胞和B细胞增强其效应功能。可以特异性识别衣壳的B细胞会释放抗体，可能导致未来重复给药时抗体介导的免疫排斥。通过在GOI质粒中表达盒的3’UTR设计miRNA结合位点，可以与细胞内的miRNA相互作用，导致转录本降解。在抗原呈递细胞中，这种设计可能会阻止转基因来源的肽段被呈递给T细胞。此外，抗CD20抗体利妥昔单抗和mTOR抑制剂雷帕霉素也可用于减少适应性免疫反应。 1 预存免疫针对rAAV衣壳的预先存在的体液免疫反应，通常通过rAAV特异性中和抗体（NAbs）来衡量，这些抗体可能源自与野生型AAV的过往接触，形成了免疫记忆。新生儿在出生后的前6个月会携带母体来源的AAV中和抗体。之后，中和抗体的滴度会逐渐下降，但在婴儿7至9个月大时，抗体滴度会再次升高。不同血清型和不同地理区域的血清阳性率差异较大，从低于10%到超过90%不等。对于rAAV基因治疗来说，这种免疫反应是最大的挑战之一，因为即使是低水平的血清阳性反应，也可能显著降低通过静脉给药的载体转基因表达效果。在与外来抗原积极交战时，一些表达IgG的B细胞会分化为长期存在的浆细胞，这些浆细胞主要驻留在骨髓中，并在感染得到控制后继续产生抗原特异性的IgG。尽管IgM水平在感染结束后会迅速下降，IgG水平却可以保持相当长的时间，成为抵抗感染的主要体液免疫屏障。 NAbs（中和抗体）在再次给药时也是一个巨大的挑战。由于rAAV基因组通常以环状游离基因组的形式存在，它们在宿主细胞每次分裂时会平均减少一半，且在宿主细胞死亡时会丢失。因此，在患者的一生中，特别是对于细胞周期活跃的器官（如肝脏）的基因治疗，可能需要多次给药。然而，重新给药时会受到由第一次给药引发的NAbs的抑制。基因治疗中rAAV衣壳-抗体的相互作用：在基因治疗中rAAV衣壳与抗体的相互作用尤为关键。通过冷冻电镜（cryo-EM）或肽扫描技术，可以捕捉到抗体与AAV衣壳表面相互作用的互补决定区（即抗体接触抗原的位置）。研究人员已经识别出一些抗原“热点”区域，比如二十面体结构的3重对称轴、5重对称轴以及2/5重对称区域等。在一项针对接受Zolgensma治疗的患者的最新研究中，约75%的抗体与2重表面结合。尽管这些发现有助于指导衣壳改造，以避开由抗体引发的预存免疫反应，但需要注意的是，rAAV相对较小，因此即使少量抗体结合到病毒衣壳上，也足以覆盖其表面并阻止病毒进入细胞。对局部与系统给药方式的影响：静脉输注最容易受到循环中rAAV特异性抗体的影响。相比之下，局部注射到免疫豁免器官（如眼睛和中枢神经系统）的方式对rAAV特异性抗体的限制较小，并且有可能进行重新给药。尽管玻璃体中的预存中和抗体（NAbs）水平远低于血清中的水平，但玻璃体中的NAb水平与血脑屏障（BBB）的完整性呈负相关关系，这一点在评估眼科基因治疗潜在影响时尤为重要。在接受ADVM-022通过玻璃体内注射的非人类灵长类动物（NHPs）中，注射了一只眼睛后，血清和注射眼睛中均出现了NAbs，但未注射的眼睛中并未出现。两个月后对另一只眼睛进行玻璃体内注射，未导致炎症加重。与第一只眼睛相比，第二只眼睛中的转基因表达趋势较低，但仍在预测范围之内。有趣的是，针对循环中NAbs的不同敏感性，可能可以作为一种策略，以限制载体在非靶组织中的感染。具体来说，在进行脑内或脑室内注射时，NAbs的存在能够阻止转基因递送到肝脏，但不会阻止其递送到中枢神经系统。筛选预存免疫：可以通过酶联免疫吸附测定（ELISA）来检测针对rAAV衣壳的总抗体（TAb）水平。为了确定患者是否符合临床试验的入组标准，许多试验采用基于细胞转导抑制（TI）的方法来评估患者血清需要稀释到什么程度才能允许最佳的rAAV感染。有时，血清中可能出现TAb阳性但TI阴性的情况，这表明并非所有AAV特异性抗体都会抑制转导。更有趣的是，有些血清TAb阴性但TI阳性，这意味着血清中存在非抗体的抑制性成分。逃避预存免疫的策略：CD20是一种在B细胞上高度表达的特异性分子，能够被利妥昔单抗（rituximab）靶向。利妥昔单抗在多个基因治疗试验中与其他免疫抑制剂（如类固醇和雷帕霉素）联合使用，旨在减少全身炎症反应以及B细胞和T细胞介导的免疫反应。然而，利妥昔单抗无法有效预防已有的体液免疫反应，因为长期存活的浆细胞不表达CD20。在rAAV外面包裹囊泡（EVs）可能有助于部分逃避中和抗体（NAbs）的作用。还可以在EVs表面加载免疫抑制分子，如CTLA-4，从而进一步抑制免疫反应。将rAAV包裹在EVs内部可能改变其对不同组织的趋向性，这可能需要对EV进行额外的修饰，类似于对rAAV衣壳的改造。这也是逃避预存免疫反应的另一种常见方法。最近，研究者探索了能够切割人类抗体的细菌内肽酶。来自化脓性链球菌的IgG降解酶Imilifadase（IdeS）已被证明能够有效消耗总IgG，并在rAAV血清阳性的非人灵长类动物（NHPs）中显著改善载体转导。来自马链球菌的IdeZ也显示出了类似的效果。此外，IdeXork，一种专有的IgG降解酶，目前正在基于rAAV的迟发性庞贝病临床试验中进行研究。多项研究表明，IdeS型酶能够提供一个5-7天的无IgG窗口期。一个潜在的问题是，IdeS在中和滴度较低时（例如，NHP中AAV3B的中和滴度约为1:108）效果最佳。在一个初始中和滴度为1:696的NHP中，IdeS将滴度降至1:88，这仍然足以抑制转基因表达。此外，针对IdeS的适应性免疫反应可能会降低其效果。借鉴移植研究的经验，二次使用IdeS可能只能提供一个24小时的治疗窗口，因为会产生抗IdeS抗体。此外，还有来自猪链球菌的IgM切割酶（IceM）和经过工程改造的IceMG，后者能够同时切割IgM和IgG。除了切割血清中游离的IgM/G外，这些酶还能从B细胞表面切割IgM，并阻断rAAV9介导的补体激活。不过，这些酶是否能转化为临床应用仍需要进一步研究。 2 补体激活补体系统由一系列高浓度的血清蛋白和相关细胞表面受体组成。在接受高剂量（约1.0 × 10^14 vg/kg）rAAV基因治疗的患者中，许多人出现了与补体激活相关的治疗相关不良事件（TEAEs），包括血小板减少、溶血性贫血、血栓微血管病（TMA）、转氨酶升高、急性肝损伤以及类似溶血性尿毒症综合征（aHUS）的肾损伤。已有因补体激活引发的死亡案例。值得注意的是，截至2022年1月13日，在超过1400名接受Zolgensma治疗的患者中，记录了9例TMA病例（约占0.6%）（https://www.fda.gov/media/126109/ download）。补体激活可以通过三种途径之一发生：经典途径（由IgM/IgG、C1q和C4介导）、替代途径（通过C3的自发水解）和凝集素途径（由甘露糖结合凝集素介导）。这三条途径最终都汇聚到C3转化酶和C5转化酶的形成，进而产生膜攻击复合体，导致细胞死亡。 rAAV输注期间补体激活的具体机制尚未完全明了。AAV2衣壳能够直接免疫沉淀C3及其裂解产物C3b和iC3b，但在体外，当rAAV颗粒的剂量达到1 × 10^14 vg/kg时，在无IgG的混合人类血清中并不会激活C3。体外实验表明，只有当存在抗AAV抗体时，AAV才能在全血中激活补体。多个临床试验观察到接受rAAV治疗的患者体内C4水平下降。此外，最近一项针对接受Zolgensma治疗患者的研究发现，单独接受类固醇治疗的患者表现出更高的TMA发生率，并且AAV9特异性IgM和IgG滴度较高，而同时接受类固醇、利妥昔单抗和雷帕霉素治疗的患者则表现出较低的抗体滴度和最小的补体激活。这些证据似乎表明，rAAV输注中的补体激活是通过经典途径发生的。然而，两个观察结果与这一假设存在一定的冲突，尚未得到充分解释。首先，在AAV初次接触的患者中，即便在rAAV特异性IgM和IgG尚未产生之前，C4水平就已较低。其次，患者在预先筛选时已被被确定为特定AAV血清型阴性。在rAAV给药后，小鼠和非人类灵长类动物（NHPs）似乎没有表现出在人类中观察到的补体激活特征。在NHPs中，即使AAV特异性IgM尚未出现，也在给药后第3天短暂出现了补体激活，表现为Bb和sC5b-9的增加，而非C4b。在小鼠中，未发表的结果显示，当AAV的剂量达到2.5 × 10^14 vg/kg时，补体激活非常轻微。最近一项在小鼠中的研究表明，当剂量达到3.0 × 10^14 vg/kg时，可检测到血清中的C3b和肝脏中的C5b-9；而在7.0 × 10^14 vg/kg的超临床剂量下，出现了轻度的血小板减少，并且补体激活的峰值出现在给药后的第3天。补体抑制策略：目前正在测试几种补体抑制剂用于rAAV基因治疗，包括阻断C5的人单克隆抗体依库珠单抗、阻断C3的肽类抑制剂APL-9421以及天然存在的血清蛋白C1酯酶抑制剂（C1-inh）。依库珠单抗已用于治疗溶血性尿毒症综合征（aHUS），并且也已用于TMA后的基因治疗患者。尽管大多数患者从TMA中恢复，但有一名患者最终因新发的金黄色葡萄球菌表皮炎感染导致急性肾损伤而死亡。依库珠单抗能够降低血清中的sC5b-9并略微增加血小板计数，但未能挽救该患者，因为补体在抗细菌防御中是必不可少的。由于C3与rAAV衣壳的相互作用促进了小鼠巨噬细胞对病毒的摄取，因此补体抑制可能会影响rAAV的转导效率。体外实验结果证实，APL-9421在NAb高的血清中能够减少人类血液白细胞对rAAV的摄取，但在NAb低的血清中没有此效应。然而， C1-inh在未免疫小鼠和免疫小鼠中分别提高了约33%和28%的肝脏转导效率。 3 天然免疫细胞的表面、内质体和细胞质中存在一些被称为天然免疫受体的模式识别受体（Pattern Recognition Receptors，PRRs），它们能够识别病原体相关分子模式（Pathogen-Associated Molecular Patterns，PAMPs），触发免疫应答。这些受体包括Toll样受体（TLRs）、RIG-I（维甲酸诱导基因-I）样受体（RLRs）、NOD样受体（NLRs）等，它们有助于宿主防御微生物感染，特别是对病毒等病原体的识别和响应至关重要。天然免疫受体通常在病原体感染后的几分钟或几小时内被激活。由于rAAV是病毒，它的一些固有特征可能会被这些天然免疫受体识别。天然免疫受体激活后会导致炎症细胞因子的产生，这些因子已被证明显著降低转基因表达，并进一步诱导适应性免疫应答。已证明与rAAV相互作用的天然免疫受体：已证实与rAAV相互作用的先天受体包括TLR-2、TLR-9、MDA5和RIG-I。TLR-2是一种细胞表面受体，能够识别多种微生物相关的配体，如脂蛋白、肽聚糖和糖脂。TLR-2还可以通过与TLR-1和TLR-6形成异二聚体，进一步扩大其配体识别范围。研究发现，rAAV2和rAAV8通过TLR-2依赖的途径在人体肝细胞中激活了NF-κB介导的细胞因子表达。TLR-9是一种内质体膜附着的受体，负责识别微生物DNA中的未甲基化CpG序列。rAAV激活TLR-9不仅导致下游TLR信号转导介导的细胞因子（如IL-6和TNF-α）的急性表达，还会促使细胞毒性CD8+ T细胞浸润，导致转导细胞的死亡。此外，通过从基于rAAV8的血友病B治疗载体中去除CpG序列，可减少中和抗体的产生。MDA5和RIG-I是细胞质中的dsRNA传感器。rAAV的3′ ITR区域可能具有合成负链RNA的启动子活性，其与正链转录本退火形成双链RNA。人体肝细胞和灵长类视网膜均高表达MDA5和RIG-I，且在体外rAAV感染后能介导IFN-β的产生。最近的一项研究表明，IL-1受体（IL-1R）-MyD88信号转导是rAAV检测的关键因素。研究发现，IL-1R−/−和MyD88−/−小鼠在注射rAAV8.OVA后并未显示出转基因特异性T细胞反应。IL-1R的配体为IL-1α和IL-1β，这些配体在炎症小体激活后被激活，而MyD88在TLRs和IL-1R的下游发挥作用。有趣的是，缺乏TLR2/3/4/9、NLRP1/3、AIM2或Caspase-1的小鼠表现出正常或仅轻微降低的转基因特异性T细胞反应，表明rAAV可能由未知的天然免疫受体识别到。减轻天然受体信号传导的策略：为减少TLR-9信号传导，可通过密码子优化去除rAAV载体中的CpG序列。然而，这种方法的一个担忧在于不同tRNA分子的丰度可能存在差异，改变其使用可能会影响蛋白折叠的动态，并增加误折叠的风险。因此，在rAAV生产过程中加入甲基转移酶或许是一个更好的替代方案。另一种选择是添加TLR-9抑制序列。哺乳动物端粒来源的ODN TTAGGG重复序列能够形成G-四联体，可通过与TLR-9结合以抑制其二聚体的形成和信号传导。携带该序列的rAAV在多种动物模型中表现出较低的免疫刺激性，减少了肝脏、肌肉和视网膜的T细胞浸润。药理学抑制天然免疫信号通路也是一种可行策略。阻断IL-1（炎症小体相关细胞因子）可以降低rAAV衣壳和GOI表达产物特异性CD8+ T细胞的比例，而抑制IL-6（TLR相关细胞因子）则减少了对rAAV衣壳的抗体反应。此外，在体外实验中抑制IRAK4（TLR信号通路中的激酶）降低了TLR-9介导的细胞因子表达，目前该策略正在进行体内测试。 4 适应性免疫适应性免疫是指抗原特异性的B细胞和T细胞反应。B细胞能够产生针对rAAV衣壳的抗体，从而使再次给药变得不可能。细胞毒性CD8+ T细胞可以识别来自GOI表达产物和rAAV衣壳的外源性肽片段，并启动对转导细胞的杀伤。CD4+ T细胞通过分泌Th1、Th2或Th17型细胞因子来辅助B细胞和细胞毒性T细胞的反应。适应性B细胞反应的形成过程与预先存在的体液免疫机制相似，因此本节将主要关注T细胞反应。 T细胞介导的不良反应：背根神经节（DRG）是沿脊髓分布的感觉神经元群，发挥传递感觉信息的关键作用。研究发现，在NHP、啮齿动物和小猪模型中，DRG损伤的发生率与剂量呈正相关。在一位人类患者中，观察到DRG毒性症状，包括感觉变化、疼痛和核磁共振成像（MRI）上DRG的增强。部分损伤可能由GOI引起，通常持续时间和影响范围有限，但严重的DRG毒性则与CD8+ T细胞的大量浸润有关，且不受类固醇的影响（https://www.fda.gov/media/152000/download）。类似地，在NHP中，系统性rAAV感染后出现的心肌炎被认为是由于心肌损伤引发的CD8+ T细胞介导的细胞毒性反应所致，表现为严重心肌炎中CD8+ T细胞的高浸润，以及酶联免疫吸附点试验中检测到的强烈的GOI特异性反应。当前的免疫抑制药物：目前，许多试验已采用包括类固醇、利妥昔单抗和雷帕霉素在内的三重免疫抑制方案。而当前用于抑制rAAV基因治疗临床试验中免疫反应的药物几乎都最初用于治疗其他疾病（如自身免疫疾病、器官移植和肿瘤），并非专为rAAV开发（表3）。这些疾病的生理机制与基于rAAV的基因治疗可能存在显著差异，因此有必要进一步研发专门针对rAAV的药物疗法。表3 目前在基因疗法试验中使用或在动物模型中正在研究的免疫抑制药物。在推进对rAAV免疫学的理解过程中，有三个关键领域值得关注：首先，关于野生型AAV的基础免疫学研究存在显著空白；其次，现有免疫学研究主要集中在原代免疫细胞、源自免疫细胞的细胞系或肿瘤细胞，而忽略了rAAV基因治疗在体内靶向的多种体细胞（如中枢神经系统细胞、视网膜细胞、肝细胞和肌肉细胞），这些细胞具有各自独特的免疫特征；第三，从动物模型获得的见解并不总能反映人类临床试验中的免疫反应。为应对这些挑战，可以考虑改进体外建模系统，如混合细胞培养、3D类器官和诱导多能干细胞。此外，CRISPR筛选技术的进步可能有助于识别参与rAAV基因递送的细胞因子。创新的体内系统也在研发中，如植入人类骨髓、肝脏和胸腺（BLT）系统的小鼠模型，有望用于监测人类天然免疫受体的激活及人类适应性免疫的形成。参考资料： 1. https://doi-org.libproxy1.nus.edu.sg/10.1038/s41392-024-01780-w 关于派真生物

基因疗法

2024-11-11

·GlobeNewswire-Health Care

MediciNova Given Notice of Monetary Damages Due Under Patent Settlement of Sanofi-Novartis

LA JOLLA, Calif., Nov. 11, 2024 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ: MNOV) and the Standard Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that it was notified by Sanofi that the Sanofi/Novartis litigation was settled. Accordingly, MediciNova is entitled to receive a certain amount of monetary damages through this settlement. Further details will be provided as they become available. Yuichi Iwaki, M.D., Ph.D., MediciNova CEO commented, “The successful resolution of the Sanofi-Novartis litigation and the resulting monetary damages due to MediciNova both validates the value of our intellectual property and provides an additional source of non-dilutive funding, which we plan to apply to supporting our ongoing clinical development programs, particularly our late-stage pipeline targeting inflammatory, metabolic, and neurodegenerative diseases. This outcome further reinforces our commitment to developing unique assets with long-term value. We remain dedicated to preserving our financial position as we continue to prudently advance our novel small molecule therapies towards commercialization." About Sanofi/Novartis litigation On March 30,2022, MediciNova, Inc. was notified that Genzyme Corporation, a subsidiary of Sanofi, filed its First Amended Complaint, which included a claim for infringement of U.S. Patent No. 9,051,542, on February 23, 2022 in a lawsuit previously filed against Novartis Gene Therapies, Inc., Novartis Pharmaceutical Corporation, and Novartis AG in the U.S. District Court for the District of Delaware. This patent, among others was included in the assignment Agreement dated December 19, 2005, between MediciNova, Inc., as successor in interest to Avigen, Inc. and Genzyme Corporation. The plaintiffs allege that the defendants infringe certain U.S. patents through the unauthorized manufacture, use, and sale of recombinant adeno-associated virus vectors (“rAAV vectors”) for their gene therapy drug Zolgensma. If Genzyme recovers any monetary damages, by way of settlement or otherwise, as a result of this litigation, then MediciNova is entitled to receive a certain portion of such monetary damages from Genzyme as per the terms of assignment agreement. About Zolgensma The U.S. Food and Drug Administration (FDA) approved Zolgensma (onasemnogene abeparvovec-xioi) on May 24, 2019. Zolgensma is a gene therapy that treats children under two years old with spinal muscular atrophy (SMA). It was the first gene therapy approved by the FDA to treat a disease. Novartis priced an infusion at $2.1 million, making it one of the priciest medicines on the market. Zolgensma has become one of Novartis’ top-sellers, generating more than $1.3 billion in annual sales in 2023. The company expects it to eventually earn between $1.5 billion and $2 billion annually. Approved in 45 countries, Zolgensma replaces the faulty gene responsible for causing spinal muscular atrophy, a condition that in its severe form robs infants of the ability to stand, sit and, eventually, breathe. Untreated, it’s typically fatal by a very young age. Zolgensma can deliver dramatic benefits, keeping children alive and in some cases helping them achieve motor and developmental milestones they otherwise wouldn’t. In the U.S, its use is limited to babies under the age of two, where it’s seen as having the greatest benefit. About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in Long COVID and substance dependence. MN 001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by, or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2023 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT: David H. Crean, Ph.D.Chief Business OfficerMediciNova, Incinfo@medicinova.com

临床2期上市批准临床3期

100 项与 Onasemnogene abeparvovec 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11559	Onasemnogene abeparvovec	M09AX	DB15528

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适应症	国家/地区	公司	日期
I型脊髓性肌萎缩症	韩国	Novartis Gene Therapies, Inc.	2021-05-28
脊髓性肌萎缩	美国	Novartis Gene Therapies, Inc.	2019-05-24

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适应症	最高研发状态	国家/地区	公司	日期
青少年脊髓性肌萎缩症	临床3期	美国	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	日本	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	澳大利亚	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	比利时	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	加拿大	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	法国	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	意大利	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	中国台湾	Novartis Gene Therapies, Inc.	2020-02-10
青少年脊髓性肌萎缩症	临床3期	英国	Novartis Gene Therapies, Inc.	2020-02-10
II型脊髓性肌萎缩	临床3期	美国	Novartis Gene Therapies, Inc.	2020-02-10

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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


NCT04851873 (SMART, MDA2024) 人工标引	临床3期	脊髓性肌萎缩	24	onasemnogene abeparvovec	淵齋積獵願鏇製遞顧獵(憲製選繭遞網艱鑰廠窪) = 積襯糧憲蓋淵淵積壓鏇鹹艱鑰夢壓艱鑰鹽築網 (糧醖齋鬱築顧襯鹹廠襯, 4.0) 更多	积极	2024-03-04
NCT05073133 (OFELIA, MDA2024) 人工标引	临床4期	脊髓性肌萎缩	16	Onasemnogene Abeparvovec	鬱積淵襯獵遞鏇鑰鹽範(膚鹽夢醖憲夢齋餘積築) = 遞壓鬱淵餘糧顧夢製觸獵鬱廠壓構築遞窪選淵 (齋壓鏇鹹艱窪齋簾範簾 ) 更多	积极	2024-03-03
MDA2024	N/A	脊髓性肌萎缩	-	Onasemnogene abeparvovec	壓簾廠醖醖壓壓鬱夢鏇(積繭蓋鏇觸鹽築觸壓艱) = Troponin I elevations observed in OA-treated patients in RESTORE appear to be transient and self-limiting and were not associated with clinically concerning cardiac adverse events 網簾選築壓範獵膚簾鏇 (糧築醖衊築鑰壓鏇夢選 )	-	2024-03-03
MDA2024	N/A	-	-	Onasemnogene abeparvovec	淵衊齋製繭積艱範範構(鹹夢蓋鬱築窪觸觸鬱壓) = Adverse events were recorded for two patients. None were serious and treatment-related, and event types were consistent with the established safety profile of OA 鑰繭窪網積鏇遞獵齋淵 (蓋範願鹹膚鏇憲艱廠鬱 ) 更多	-	2024-03-03
RESTORE Registry (MDA2024)	N/A	脊髓性肌萎缩	31	Onasemnogene abeparvovec	鬱糧遞顧醖鬱糧壓顧積(顧構繭夢蓋衊壓膚鹹願) = Two deaths were recorded, neither related to treatment 淵築憲膚獵構蓋觸齋遞 (鬱壓衊蓋獵糧願顧觸壓 ) 更多	积极	2024-03-03
MDA2024	N/A	脊髓性肌萎缩	-	Onasemnogene abeparvovec (OA)	餘淵觸襯範鑰繭憲衊壓(簾範膚網壓繭艱蓋網範) = 鏇構顧壓夢蓋憲鬱壓顧鬱鏇襯範範積製齋鑰餘 (夢衊餘鹹鹽糧顧蓋獵窪 )	-	2024-03-03
MDA2024	N/A	脊髓性肌萎缩	-	Risdiplam (EVRYSDI)	餘淵觸襯範鑰繭憲衊壓(簾範膚網壓繭艱蓋網範) = 鹽艱鹹築遞鹽觸顧廠淵鬱鏇襯範範積製齋鑰餘 (夢衊餘鹹鹽糧顧蓋獵窪 )	-	2024-03-03
SPR1NT (AAN2023)	临床3期	脊髓性肌萎缩 SMN2	29	Onasemnogene Abeparvovec	鏇網襯夢願繭衊衊製憲(獵網願範繭餘鹽鹹繭壓) = 顧遞願鹽鹹鬱範鏇齋壓餘憲繭壓顧鹹選襯願觸 (構淵鏇遞鹹願網簾餘襯 )	-	2023-04-25
SPR1NT (AAN2023)	临床3期	脊髓性肌萎缩 SMN2	29	Onasemnogene Abeparvovec	鏇網襯夢願繭衊衊製憲(獵網願範繭餘鹽鹹繭壓) = 構鏇廠鬱繭製顧廠鑰構餘憲繭壓顧鹹選襯願觸 (構淵鏇遞鹹願網簾餘襯 )	-	2023-04-25
AAN2023	N/A	脊髓性肌萎缩 SMN2	-	Onasemnogene-abeparvovec	鹹餘廠獵顧範衊蓋餘簾(膚顧壓齋艱憲觸獵範襯) = 齋齋網糧遞願淵顧獵鹹顧襯範築淵夢範夢鏇衊 (簾範觸餘窪廠窪構網夢 ) 更多	-	2023-04-25
NCT04042025 (LT-002, AAN2023)	临床3期	脊髓性肌萎缩	81	Intravenous onasemnogene abeparvovec	獵網壓構觸壓壓獵選鹹(顧鏇網選築製簾餘簾鹽) = The most frequently reported TEAEs were gastroenteritis, nasopharyngitis, pneumonia, respiratory distress, and viral infection 蓋齋壓繭憲網鑰餘壓鏇 (淵築鬱觸觸醖選鹹衊網 )	积极	2023-04-25
NCT04042025 (LT-002, AAN2023)	临床3期	脊髓性肌萎缩	81	Intrathecal onasemnogene abeparvovec		积极	2023-04-25
SPR1NT (MDA2023)	N/A	脊髓性肌萎缩 SMN2 copies	29	Onasemnogene abeparvovec	選淵醖壓範範窪鑰積糧(糧製網顧鏇窪鹹餘壓醖) = 選獵壓淵淵製憲糧獵鑰簾衊顧範觸壓願醖餘壓 (蓋蓋願觸構遞襯衊顧願 ) 更多	积极	2023-03-19