A Phase 1 Open-label Intrathecal Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by a Mutation in the AP4M1 Gene

This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity.
The secondary outcome will be a preliminary exploration of efficacy of the treatment.
MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg.
The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.

开始日期2022-03-11

申办/合作机构

The Hospital for Sick Children

100 项与 AP4 相关的临床结果

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100 项与 AP4 相关的转化医学

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0 项与 AP4 相关的专利（医药）

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230

项与 AP4 相关的文献（医药）

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Metabolic alterations in fibroblasts of patients presenting with the MPAN subtype of neurodegeneration with brain iron accumulation (NBIA)

Review

作者: Cudna, Agnieszka ; Wydrych, Agata ; Wieckowski, Mariusz R ; Pierzynowska, Karolina ; Jakubek-Olszewska, Patrycja ; Pinton, Paolo ; Węgrzyn, Grzegorz ; Janikiewicz, Justyna ; Rydzewski, Marcel ; Cwyl, Maciej ; Lebiedzińska-Arciszewska, Magdalena ; Cyske, Zuzanna ; Skowrońska, Marta ; Koopman, Werner J H ; Kurkowska-Jastrzębska, Iwona ; Pakuła, Barbara ; Gaffke, Lidia ; Rintz, Estera ; Dobosz, Aneta M ; Dobrzyń, Agnieszka

Mutations in the following genes: PANK2, PLA2G6, C19orf12, WDR45, CP, FA2H, ATP13A2, FTL, DCAF17, and CoASY are associated with the development of different subtypes of inherited rare disease Neurodegeneration with Brain Iron Accumulation (NBIA). Additionally, recently described mutations in FTH1, AP4M1, REPS1, SCP2, CRAT and GTPBP2 affecting iron and lipid metabolism also are thought to be involved in NBIA development. Four main subtypes, pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN), are responsible for up to 82 % of all NBIA cases. Here we studied fibroblasts from 11 patients with pathogenic mutations in C19orf12, and demonstrate various cellular aberrations. Differences between fibroblasts from healthy individuals and MPAN patients were potentiated when cells were grown under oxidative phosphorylation (OXPHOS) promoting condition suggesting an impaired metabolic flexibility. The extent of some of the cellular aberrations quantitatively correlated with disease severity, suggesting their involvement in the NBIA pathomechanism.

2024-12-01·Neurobiology of Aging

The links among age, sex, and glutathione: A cross-sectional magnetic resonance spectroscopy study

Article

作者: O’Gorman-Tuura, Ruth ; Treyer, Valerie ; Bachmann, Dario ; Zuber, Isabelle ; Studer, Sandro ; Müller, Susanne ; Rauen, Katrin ; O'Gorman-Tuura, Ruth ; Michels, Lars ; Buchmann, Andreas ; Hock, Christoph ; Gruber, Esmeralda ; Saake, Antje ; Gietl, Anton

Glutathione (GSH) is a brain marker for oxidative stress and has previously been associated with cerebral amyloid deposition and memory decline. However, to date, no study has examined the links among GSH, sex, age, amyloid, and Apolipoprotein E (APOE) genotype in a large non-clinical cohort of older adults. We performed APOE genotyping, magnetic resonance spectroscopy (MRS) as well as simultaneous positron emission tomography with the radiotracer Flutemetamol (Amyloid-PET), in a group of older adults. The final analysis set comprised 140 healthy older adults (mean age: 64.7 years) and 49 participants with mild cognitive impairment (mean age: 71.4 years). We recorded metabolites in the posterior cingulate cortex (PCC) by a GSH-edited MEGAPRESS sequence. Structural equation modeling revealed that higher GSH levels were associated with female sex, but neither APOE- epsilon 4 carrier status nor age showed significant associations with GSH. Conversely, older age and the presence of an APOE4 allele, but not sex, are linked to higher global amyloid load. Our results suggest that the PCC shows sex-specific GSH alterations in older adults.

2024-10-01·Progress in Neurobiology

Corrigendum to “The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for hereditary spastic paraplegia” [Progr. Neurobiol. 234(2024)102575]

作者: Caracci, Mario O ; Farfán, Pamela ; Cavieres, Viviana A ; De Pace, Raffaella ; Fuentealba, Luz M ; Marzolo, María-Paz ; Pástor, Tammy P. ; Mardones, Gonzalo A. ; Bonifacino, Juan S. ; Cavieres, Viviana A. ; Caracci, Mario O. ; Alarcón-Godoy, Carlos ; Bonifacino, Juan S ; Pizarro, Héctor ; Fuentealba, Luz M. ; Santibañez, Natacha ; Mardones, Gonzalo A ; Pástor, Tammy P

项与 AP4 相关的新闻（医药）

2024-07-08

·派真生物PackGene

一周要闻丨基因治疗要闻速递第110期

行业动态速览热点聚焦 01 只有一个患者的临床试验！AAV基因治疗对抗无药可治的超罕见绝症痉挛性截瘫50型（spastic paraplegia type 50，SPG50）是一种超罕见的疾病，全球患儿数量只有约80人，而在加拿大仅有迈克尔一人被报道患有SPG50。SPG50患者会经历发育迟缓、言语功能障碍以及进行性的四肢瘫痪，通常活不到成年阶段。在2022年，迈克尔参与了以AAV为基础的SPG50基因疗法临床试验，同时他也是这项试验唯一的患者。这项1期临床试验的结果已经以“AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient”为题，发表在《自然-医学》上，结果支持了基因疗法拯救迈克尔计划的初步成功。推荐阅读：只有一个患者的临床试验！对抗无药可治的超罕见绝症，7岁的他迎来治愈曙光 02 利用mRNA瞬时构建TCR-T细胞，治疗晚期难治性高MSI结直肠癌患者！结直肠癌（CRC）是全球第三大常见癌症，尽管局部性 CRC 生存率高，但转移性CRC的5年生存率仅约为11%。近期，挪威奥斯陆大学医学院研究团队报道了在患有 LS 和晚期转移性 MSI-H CRC 的患者中，首次使用 mRNA 电穿孔进行瞬时表达 Radium-1 TCR 在临床患者中应用，相关文章以简报形式，发表在Cell ASGCT系列杂志《Molecular Therapy》上。推荐阅读：利用mRNA瞬时构建TCR-T细胞，治疗晚期难治性高MSI结直肠癌患者！ 03超70%患者达主要终点！潜在“first-in-class"CAR-T疗法积极临床结果公布近日，Cartesian Therapeutics宣布了其在研mRNA细胞疗法Descartes-08在全身性重症肌无力（MG）患者中的2b期临床试验的积极顶线结果。推荐阅读：超70%患者达主要终点！潜在“first-in-class"CAR-T疗法积极临床结果公布 04 CDE公开征求意见！规范腺相关病毒载体基因治疗产品非临床研究近日，中国国家药品监督管理局（NMPA）药品审评中心（CDE）发布了《腺相关病毒载体基因治疗产品非临床研究技术指导原则（征求意见稿）》，旨在规范并促进腺相关病毒（AAV）载体基因治疗产品的非临床研究，为该类产品的临床试验和上市提供科学依据。推荐阅读：CDE公开征求意见！规范腺相关病毒载体基因治疗产品非临床研究创新突破 01 AAV递送工程，最新Science！美国怀特海德生物医学研究所Jonathan S. Weissman和MIT/哈佛大学Sonia M. Vallabh等人开发了一种名为CHARM的紧凑表观基因组编辑器，单个AAV就能实现对其的有效递送。在小鼠实验中，CHARM可以敲低全脑中80%以上的朊病毒基因，同时不会改变潜在的DNA序列。该编辑器可以在沉默靶标后实现自我沉默，从而限制长期表达的潜在不利影响。CHARM代表了一种治疗模式，可应用于由有害蛋白质的毒性积聚引起的一系列其他疾病。因此，CHARM最终可能对人类产生类似于碱基编辑、先导编辑等工具的巨大影响。推荐阅读：AAV递送工程，最新Science！ 02 减毒病毒疗法助力癌症治疗！近日，一篇发表在国际杂志Journal of Clinical Investigation上题为“An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I”的研究报告中，来自美国西北大学等机构的科学家们通过研究发现，一种减毒的淋巴细胞性脑膜脊髓炎病毒（LCMV）能够有效清除小鼠体内的肿瘤，并使幸存小鼠对后续肿瘤发展具备更强抵抗力。研究结果揭示了特殊LCMV载体的强大抗肿瘤效应，并揭示了其抗肿瘤疗效背后的多种分子机制，为癌症治疗提供了新思路。推荐阅读：减毒病毒疗法助力癌症治疗！ 03 苏州儿童医院团队鉴定新的神经母细胞瘤超级增强子近日，苏州大学附属儿童医院潘健和张子木团队在 Neuro-Oncology 上发表题为 Super-enhancer-driven IRF2BP2 enhances ALK activity and promotes neuroblastoma cell proliferation 的文章，鉴定出一个由NB主转录因子簇MYCN, MEIS2和HAND2 调节激活的新SE区域，导致靶基因IRF2BP2的异常高表达。IRF2BP2能够与该NB主转录因子簇之间形成正反馈回路，从而在NB中建立稳定持续的高水平IRF2BP2的表达。此外，IRF2BP2还能够与先驱因子AP-1家族成员通过调节NB易感基因ALK的染色质可及性，维持NB细胞增殖与存活。这项研究为NB生物学提供了新的见解，并有可能为NB下调ALK提供替代策略。推荐阅读：苏州儿童医院团队鉴定新的神经母细胞瘤超级增强子资本速递 01 14.5亿欧元！GSK与mRNA巨头达成协议 7月4日，葛兰素史克(LSE/NYSE: GSK) 与 CureVac N.V. (Nasdaq: CVAC)宣布，两家公司已将现有合作重组为一项新的授权协议，使双方能优先投资及专注各自的mRNA开发活动。根据协议条款，CureVac将获得4亿欧元的预付款，以及至多10.5亿欧元的开发、监管和销售里程碑以及分层版税，累计近15亿欧元（117.68亿人民币，以最新汇率计算）的款项。根据新的协议条款，GSK将全面负责以上候选疫苗的开发和生产。GSK将拥有全球商业化候选疫苗的权利。推荐阅读：14.5亿欧元！GSK与mRNA巨头达成协议 02 1.7亿美元B轮融资！创新基因疗法注册性试验已启动近日，眼科基因治疗公司Beacon Therapeutics宣布已完成1.7亿美元的 B轮融资。该融资由Forbion领投，TCGX和Advent Life Sciences参与，现有投资者Syncona Limited、Oxford Science Enterprises、牛津大学也参与其中。这些资金将用以支持Beacon用于治疗X连锁视网膜色素变性（XLRP）的主打在研基因疗法AGTC-501的持续临床开发，并支持该公司的干性老年性黄斑变性（dAMD）项目的1/2期临床试验。推荐阅读：1.7亿美元B轮融资！创新基因疗法注册性试验已启动 03 Cartesian LNP-mRNA细胞疗法临床成功，新获融资1.3亿美金！近日，Cartesian Therapeutics宣布签订了一份证券购买协议，用于私人投资公开股权（“PIPE”）融资，预计将为公司带来大约1.30亿美元的总收益。推荐阅读：Cartesian LNP-mRNA细胞疗法临床成功，新获融资1.3亿美金！参考资料： 1.https://mp.weixin.qq.com/s/pbFanDicHXsfZAAXnHZW7Q 2.https://mp.weixin.qq.com/s/GkEznBO7lvdlTThW362Erg 3.https://mp.weixin.qq.com/s/b-q0nD0P1VgnX7wlv8URnA 4.https://finance.sina.com.cn/stock/med/2024-07-07/doc-incchkam5612250.shtml 5.https://mp.weixin.qq.com/s/TO5oI7Nw1cz1tu5WkVFgbw 6.https://mp.weixin.qq.com/s/1lMb-HSL-sia6Aho0qUKCw 7.https://mp.weixin.qq.com/s/7z3SMvOeAFlrZYfdXw3kPw 8.https://mp.weixin.qq.com/s/gT_omNuemkJLTux5e6Bhjw 9.https://mp.weixin.qq.com/s/sfYhDx1ZdkS4RWdPF_oiBw 10.https://mp.weixin.qq.com/s/T9swMSo3FHpn7wrWK1xHWg 关于派真生物

细胞疗法基因疗法信使RNA免疫疗法临床1期

2024-07-05

·药明康德

只有一个患者的临床试验！对抗无药可治的超罕见绝症，7岁的他迎来治愈曙光

▎药明康德内容团队编辑 “直到时间尽头，我们也要找到拯救儿子的方法。”皮罗沃拉基斯（Pirovolakis）夫妇面对医生时，言语无比坚定。他们的孩子迈克尔（Michael）于2017年来到人世，谁也没有料到这个普通又幸福的家庭后面即将会迎来狂风骤雨。大约在迈克尔5个月时，他的母亲察觉到孩子有点难以言说的不对劲，迈克尔在抬头或者举起手指时总是有气无力。在去往医院后，医生让迈克尔接受了肌张力的训练，之后迈克尔的症状有了一定的好转。但医生仍然表示出了他们的担忧，因为后续检测显示迈克尔的大脑白质和胼胝体有着明显异常。也是这个时刻，迈克尔的病情急转直下，训练带来的改善成果完全消失，并且他还产生了癫痫的症状。很明显这不是简单的肌张力问题，找到迈克尔真正的病因已经刻不容缓。 ▲迈克尔在加拿大多伦多病童医院（图片来源：参考资料[2]，credit：The Hospital For Sick Children） 2019年，分析结果显示迈克尔的AP4M1基因出现了突变，这直接导致了衔接蛋白复合体4的功能缺陷。这类基因缺陷疾病也被称作痉挛性截瘫50型（spastic paraplegia type 50，SPG50），患者会经历发育迟缓、言语功能障碍以及进行性的四肢瘫痪，通常活不到成年阶段。从患病率来说，SPG50是一种超罕见的疾病，全球患儿数量只有约80人，而在加拿大仅有迈克尔一人被报道患有SPG50，很明显现有疗法无法帮到迈克尔。为了拯救自己的孩子，皮罗沃拉基斯夫妇成立了一个“治愈SPG50”（CureSPG50）的基金会，为迈克尔募集到了大量治疗费用，同时加拿大多伦多病童医院（The Hospital for Sick Children，SickKids）的医生开始全力为迈克尔设计一种可行的治疗方案。 ▲从确诊到基因疗法开展期间的时间线（图片来源：参考资料[1]）幸运的是，SPG50并非没有逆转的可能。它的病因源头AP4M1基因长度并不长，只有1359个碱基对，这让基因疗法有了介入和发挥的可能性。借助腺相关病毒（AAV）载体，医生可以将正确的AP4M1基因输送进迈克尔体内，当AAV进入细胞后会在细胞核内转录和翻译携带的健康AP4M1基因，进而帮助恢复正常的AP4M1蛋白功能。在2022年，迈克尔参与了以AAV为基础的SPG50基因疗法临床试验，同时他也是这项试验唯一的患者。研究人员将携带正常AP4M1基因的AAV载体注射到了迈克尔的脑脊液中，这些AAV载体会迅速地前往神经细胞发挥作用。现在，这项1期临床试验的结果已经以“AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient”为题，发表在《自然-医学》上。根据论文，研究者注射的AAV达到了1×1015载体基因组（vg），也是目前通过脑脊液注射的最大病毒载量。由于迈克尔原本缺乏正确的AP4M1蛋白，为了避免突然大量出现的健康蛋白引起免疫反应，研究者还额外给其进行了AP4M1蛋白免疫抑制治疗。在治疗12个月后，迈克尔并没有展示出严重的不良反应，期间他经历过中性粒细胞减少症和腹痛症状，但都很快地恢复了过来，分析显示他的腹痛症状来自艰难梭菌感染和抗生素副作用。与此同时，各项评估数据显示迈克尔的各项疾病进展中止了，脑部和脊柱没有炎症变化，大脑萎缩没有进展。此外，迈克尔的疾病症状出现了改善的信号，在治疗前他的下肢痉挛较为严重，仅可以爬行和独自短暂在桌旁站立。 ▲基因疗法让迈克尔多个指标得到改善（图片来源：参考资料[1]）而在治疗期终点，迈克尔已经可以自己用脚后跟站立了，并且能站立更长时间，也可以使用辅助装置行走，这在治疗之前都是无法做到的。发育评估也显示，他的运动行为有所改善，迈克尔父母也近一年没有反馈过他发生跌倒、癫痫现象。这些结果都支持了基因疗法拯救迈克尔计划的初步成功。从确诊到使用上基因疗法，医生与研究人员只花费了约3年的时间，这也向我们证明了基因疗法存在快速研发、使用的可能性，这种速度对开展个体化治疗有重要意义。在迈克尔父母眼中，这只是征服SPG50的一个起点，他们的基金会仍然会继续执行下去，为后续临床试验做好准备，“这不仅仅只是拯救迈克尔，也是为未来更多SPG50患儿带去希望。” 参考资料： [1] Dowling, J.J., Pirovolakis, T., Devakandan, K. et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med (2024). https://doi.org/10.1038/s41591-024-03078-4 [2] Gene therapy halts progression of rare genetic condition in young boy. Retieved July 1, 2024 from https://www.eurekalert.org/news-releases/1049675 [3] Battling SPG50 and changing the world. Retrieved July 1, 2024 from https://www.jax.org/news-and-insights/2022/August/battling-spg50-and-changing-the-world# 本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

基因疗法临床结果临床1期

2023-09-28

·GlobeNewswire-Health Care

Viralgen Vector Core and Elpida Therapeutics partner to manufacture gene therapy medicines for anticipated Spastic Paraplegia 50 (SPG50) and Charcot-Marie-Tooth disease type 4J (CMT4J) clinical trials

Trial participants with Spastic Paraplegia 50 (SPG50) and Charcot-Marie-Tooth disease type 4J (CMT4J) could benefit from this joint effort to manufacture new gene therapies that utilize adeno-associated virus serotype 9 (AAV9) to deliver corrected genesSAN DIEGO, Sept. 28, 2023 (GLOBE NEWSWIRE) -- Viralgen Vector Core (Viralgen) and Elpida Therapeutics (Elpida Tx) have partnered to manufacture gene therapies for use in clinical trials sponsored by Elpida Tx involving patients living with SPG50 or CMT4J. It is anticipated that these trials will take place at various sites in North America and Europe and will explore potential safety and efficacy of the new treatments to be manufactured, as well as potential quality of life improvements. SPG50 is a rare disease caused by mutations in the adaptor protein complex-4 mu 1 subunit (AP4M1), which is a protein responsible for intracellular vesicle trafficking, specifically the sorting and transport of membrane proteins within cells. The disease symptoms of children with SPG50 begin with low muscle tone, microcephaly (small head) and epilepsy, then progress to affect the entire body, resulting in intellectual disabilities and movement/neurological abnormalities. This rare disease is known to affect only around 90 people worldwide.1 Charcot-Marie-Tooth disease type 4J (CMT4J) is an autosomal recessive, potentially severe form of CMT disease caused by mutations of the lipid phosphatase FIG4, a protein involved in the regulation of phosphoinositide lipids and membrane trafficking within cells. The same CMT4J genotype can present symptoms ranging from mild clinical signs to severe disability.2 The partnership between Viralgen and Elpida Tx is expected to enable the efficient manufacture of the adeno-associated vector serotype 9 (AAV9) based therapies for use in Elpida Tx's anticipated multi-site clinical trials. Viralgen will manufacture these therapies using its production process with the Pro10TM cell line, which is exclusively licensed from AskBio and has been found to increase scalability, performance, and yield of AAV therapies.3 Terry Pirovolakis, Founder and CEO of Elpida Tx, remarks that "Viralgen is truly an amazing partner, demonstrating their genuine commitment to advance potential therapies for impacted patients. We feel so grateful and honored to be working with such an incredible partner." About Elpida Therapeutics Elpida Tx's mission aims to address the current significant unmet medical needs of patients with ultra-rare diseases. Through leveraging scientific advancements and the now well-established safety and understanding of certain gene therapies, Elpida Tx aims to put cures in reach of families and children who desperately and urgently need them. Elpida Tx's business model focuses on partnerships that promote efficiency and the chance to treat a greater number of patients, while being self-sustaining and replicable. Elpida Tx specifically focuses on advancing programs that traditional biotech companies find difficult to bring through to completion. The company pipeline includes programs that were deprioritized by biotech companies or that did not receive biotech investment to advance due to small patient populations, but which have excellent scientific data on which to build a program and springboard the science and opportunity. Elpida Tx plans to incorporate three more CNS programs into its initial program pipeline within the next six months through an application process designed for academic institutions and foundations. About Viralgen Vector CoreViralgen is a Contract Development and Manufacturing Organization (CDMO) founded in 2017 and exists as an independently operated subsidiary of AskBio, which is wholly owned and independently operated as a subsidiary of Bayer AG. As a manufacturer of Current Good Manufacturing Practice (cGMP) certified AAV, Viralgen offers the Pro10™ based suspension manufacturing platform, a technology licensed from AskBio and developed by Chief Technical Officer Josh Grieger, PhD, and Co-Founder R. Jude Samulski, PhD, at University of North Carolina. The Pro10™ platform has been found to increase scalability, performance, and yield of AAV therapies 3. Located in Spain, in the Gipuzkoa Science and Technology Park, Viralgen produces AAV gene therapy treatments for pharmaceutical and biotech companies with the aim of accelerating the delivery of new treatments that may improve patients' lives. The company's clinical facilities have four cGMP manufacturing suites, with 250-liter and 500-liter bioreactors. In 2020, Viralgen expanded within the Scientific Park by constructing a new building with three modules for large-scale commercial manufacturing. Each module of the state-of-the-art space includes three cGMP suites with a manufacturing capacity of >2,000 liters. The first module, which includes a suite dedicated to fully automated fill and finish operations, has received cGMP certification by the Spanish Agency for Medicines and Medical Devices (AEMPS) as part of the EMA network. For more information, visit viralgenvc.com. References:1 J Clin Invest. 2023 May 15; 133(10): e170226. 10.1172/JCI1702262 Brain. 2011 Jul; 134(7): 1959-1971. 10.1093/brain/awr1483 Mol Ther. 2016 Feb;24(2):287-297. doi: 10.1038/mt.2015.187. Epub 2015 Oct 6. 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