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Clinical Trial Results Provide the Rationale to Protect Dual HIV-specific T Cells with a Signaling-Defective HIV Fusion Inhibitor. 临床试验结果提供了用信号缺陷HIV融合抑制剂保护双HIV特异性T细胞的基本原理。
IF 12.4 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-10 DOI: 10.1016/j.ymthe.2026.01.006
Pablo Tebas,Julie K Jadlowsky,Yuqi Zhou,M Betina Pampena,George J Leslie,Nan Liu,Sriram Srivatsa,Colby R Maldini,Jingxin Wang,Chungdhak Jaming Tsang,Ola Mohamed,Josephine Romano,Beth Haggarty,Gabriela Plesa,Avery L Gaymon,Andrea L Brennan,Elizabeth Veloso,Bruce L Levine,Mary E Putt,Irina Kulikovskaya,Vanessa Gonzalez,Joseph A Fraietta,Michael R Betts,James A Hoxie,James L Riley
Coupling the HIV fusion inhibitor C34 with CXCR4 (C34-CXCR4) protected CD4 T cells from all strains of HIV. Escape from C34-CXCR4 expression proved difficult, requiring more than 21 serial passages, mutations at conserved gp41 sites, and a complete loss of Vpu activity. A dose-escalation, Phase I clinical trial was performed in which up to 10 billion C34-CXCR4 expressing T cells were infused into people with HIV (PWH). While these infusions were safe, we observed limited persistence of these C34-CXCR4 T cells, lack of reconstitution of HIV-specific CD8 T cell responses, and no effect on time to viral rebound after an analytical treatment interruption. We hypothesized that inappropriate expression of a signaling competent chemokine receptor resulted in the limited persistence of these engineered T cells so we screened several C34-CXCR4 mutants to identify those that could not respond to CXCL12 and still could mediate potent anti-viral activity. A single mutation (D97N) in CXCR4 fulfilled both criteria. T cells co-expressing Dual HIV-specific CARs and C34-CXCR4 D97N maintained high C34-expression in vivo and controlled HIV replication better than unprotected Dual CAR T cells, suggesting that this C34-CXCR4 D97N construct should be considered for future clinical development.
将HIV融合抑制剂C34与CXCR4偶联(C34-CXCR4)可保护CD4 T细胞免受所有HIV毒株的感染。从C34-CXCR4的表达中逃脱被证明是困难的,需要超过21个连续传次,在保守的gp41位点发生突变,并且Vpu活性完全丧失。在一项剂量递增的I期临床试验中,将多达100亿个表达C34-CXCR4的T细胞输注到HIV (PWH)患者体内。虽然这些输注是安全的,但我们观察到这些C34-CXCR4 T细胞的持久性有限,缺乏hiv特异性CD8 T细胞反应的重构,并且在分析性治疗中断后对病毒反弹的时间没有影响。我们假设信号化因子受体的不适当表达导致了这些工程T细胞的有限持久性,因此我们筛选了几个C34-CXCR4突变体,以确定那些对CXCL12没有反应但仍能介导有效抗病毒活性的突变体。CXCR4中的一个单一突变(D97N)满足这两个标准。共表达Dual HIV特异性CARs和C34-CXCR4 D97N的T细胞在体内保持了较高的c34表达,并且比未受保护的Dual CAR - T细胞更好地控制了HIV复制,这表明该C34-CXCR4 D97N构建物应被考虑用于未来的临床开发。
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引用次数: 0
SLIT2 as a Key Regulator and Therapeutic Target in Liver Injury. SLIT2作为肝损伤的关键调控因子和治疗靶点。
IF 12.4 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-10 DOI: 10.1016/j.ymthe.2026.01.010
Yong Won Choi,Jae Ho Choi,Young-Sam Lee,Jinju Jeong,Eunho Kang,So Hyun Park,Young-Kyoung Lee,Soon Sang Park,Hee Young Kang,Young Hwa Kim,Tae Jun Park
Drug-induced liver injury accounts for approximately 10% of acute hepatitis and up to 50% of acute liver failure. Despite its clinical significance, treatment remains largely limited to cessation of the offending agent. SLIT/ROBO signaling, known for roles in organ development, angiogenesis, leukocyte migration, and cancer metastasis, has demonstrated protective effects against various organ damage. In mouse models of liver injury induced by acetaminophen (APAP), thioacetamide, bile duct ligation, and serum from patients with toxic liver disease, Slit2 expression significantly increases, while Slit1 and Slit3 remain unchanged. Liver-specific Slit2 knockdown exacerbates liver injury, whereas recombinant SLIT2 alleviates liver damage by reducing oxidative stress via CYP2E1 downregulation and suppressing inflammation through NF-κB inhibition. Notably, among ROBO receptors, only ROBO4 was induced in hepatocytes after APAP exposure. ROBO4 knockdown eliminates the hepatoprotective effects of SLIT2, highlighting the importance of SLIT2/BOBO4 signaling in toxic liver injury. Furthermore, a novel Slit2-derived peptide-5 (SP5), designed from the ROBO4-binding LRR2 domain, significantly reduces liver damage and inflammation. Notably, both recombinant SLIT2 and SP5 confer hepatoprotection even when administered 24 hours after APAP challenge. These findings suggest that SLIT2/ROBO4-targeted therapies may offer a promising approach for preventing fulminant hepatitis in the context of toxic liver injury.
药物性肝损伤约占急性肝炎的10%,高达急性肝衰竭的50%。尽管它具有临床意义,但治疗仍然主要局限于停止犯罪剂。众所周知,SLIT/ROBO信号在器官发育、血管生成、白细胞迁移和癌症转移中起着重要作用,并已证明对各种器官损伤具有保护作用。在对乙酰氨基酚(APAP)、硫代乙酰胺、胆管结扎和中毒性肝病患者血清诱导的小鼠肝损伤模型中,Slit2表达显著升高,而Slit1和Slit3表达不变。肝脏特异性Slit2敲低会加重肝损伤,而重组Slit2则通过下调CYP2E1降低氧化应激,抑制NF-κB抑制炎症,从而减轻肝损伤。值得注意的是,在ROBO受体中,APAP暴露后只有rob4在肝细胞中被诱导。rob4敲低消除了SLIT2的肝保护作用,突出了SLIT2/BOBO4信号在中毒性肝损伤中的重要性。此外,一种新的slit2衍生肽-5 (SP5),由robo4结合LRR2结构域设计而成,可显著减少肝损伤和炎症。值得注意的是,重组SLIT2和SP5即使在APAP攻击后24小时给药也具有肝保护作用。这些发现表明,SLIT2/ robo4靶向治疗可能为预防中毒性肝损伤背景下的暴发性肝炎提供了一种有希望的方法。
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引用次数: 0
M2 macrophage exosomes reverse heart failure post-myocardial infarction by suppressing type 1 interferon signaling in myeloid cells. M2巨噬细胞外泌体通过抑制髓细胞中1型干扰素信号逆转饮食性心肌梗死小鼠心功能下降
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.010
Martin Ng, Alex S Gao, Tuan Anh Phu, Ngan K Vu, Robert L Raffai

Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncover that exosomes produced by human Tohoku Hospital Pediatrics-1 (THP-1) macrophages cultured with the cytokine interleukin-4 (THP1-IL4-exo) reverse cardiac functional decline in mice that developed MI in response to diet-induced occlusive coronary atherosclerosis. The therapeutic benefits of THP1-IL4-exo stem from their ability to drive transcriptional reprogramming of inflammatory responses in myeloid cells. Notably, repeated infusions of THP1-IL4-exo led to the suppression of type 1 interferon signaling in circulating Ly-6Chi monocytes as well as in myeloid cells within the bone marrow and cardiac tissue. In vitro studies with primary macrophages stimulated with double-stranded DNA confirmed an ability for THP1-IL4-exo to confer suppression of type 1 interferon-mediated immune activation and inflammation. Collectively, these benefits contribute to the control of myelopoiesis, recruitment of cardiac myeloid cells, and preservation of populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel anti-inflammatory and tissue repair therapeutics to preserve cardiac function post-MI.

有效的治疗策略来缓解心肌梗死(MI)引起的心力衰竭在心血管医学中仍然是一个未满足的需求。在这项研究中,我们发现由细胞因子IL-4 (THP1-IL4-exo)培养的人THP-1巨噬细胞产生的外泌体,逆转了饮食诱导的闭塞性冠状动脉粥样硬化引起的心肌梗死小鼠的心功能下降。THP1-IL4-exo的治疗益处源于它们能够驱动髓细胞炎症反应的转录重编程。值得注意的是,反复输注THP1-IL4-exo导致循环中的Ly-6Chi单核细胞以及骨髓和心脏组织内的髓细胞中的1型干扰素信号传导受到抑制。用双链DNA刺激原代巨噬细胞的体外研究证实,THP1-IL4-exo能够抑制1型干扰素介导的免疫激活和炎症。总的来说,这些益处有助于控制骨髓生成,心脏髓细胞募集,并保持常驻心脏巨噬细胞群,共同减轻心脏炎症,不良心室重构和心力衰竭。我们的研究结果介绍了THP1-IL4-exo,一种m2 -巨噬细胞外泌体,作为一种新的抗炎和组织修复疗法来保护心肌梗死后的心脏功能。
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引用次数: 0
Langerhans cell-targeted protein delivery enhances antigen-specific cellular immune response. 朗格汉斯细胞靶向蛋白递送增强抗原特异性细胞免疫反应。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-10-04 DOI: 10.1016/j.ymthe.2025.10.008
Ramona Rica, Klara Klein, Litty Johnson, Gabriele Carta, Mirza Sarcevic, Freyja Langer, Christoph Rademacher, Robert Wawrzinek, Federica Quattrone, Florian Sparber

Targeted antigen delivery to immune cells, particularly dendritic cells, has emerged as a promising strategy to enhance therapeutic efficacy of vaccines, while minimizing adverse effects associated with conventional immunization. In this study, we use our previously described small glycomimetic molecule that is selectively recognized by the Langerhans cell (LC)-specific surface receptor Langerin and demonstrate specific delivery of protein antigens to these specialized dendritic cells. Our results show that Langerin-mediated antigen delivery significantly enhances the immune response in vivo, resulting in increased expansion and activation of antigen-specific T cells, compared to immunization with unmodified antigen. We demonstrate the feasibility of our LC-targeted platform for immune cell-specific immunization with protein antigen and underscore the potential of LCs as an access point for next-generation vaccines and immunotherapies.

靶向抗原递送到免疫细胞,特别是树突状细胞,已成为一种有希望的策略,以提高疫苗的治疗效果,同时尽量减少与常规免疫相关的不良影响。在这项研究中,我们使用我们之前描述的小的拟糖分子,选择性地识别朗格汉斯细胞(LC)特异性表面受体Langerin,并展示了特异性的蛋白质抗原递送到这些特化的树突状细胞。我们的研究结果表明,与未经修饰的抗原免疫相比,朗格林介导的抗原递送显著增强了体内的免疫反应,导致抗原特异性T细胞的扩增和活化增加。我们证明了lc靶向蛋白抗原免疫细胞特异性免疫平台的可行性,并强调了lc作为下一代疫苗和免疫疗法接入点的潜力。
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引用次数: 0
Response to the FDA's proposed pathway for individualized genetic therapies. 对FDA提出的个体化基因治疗途径的回应。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-12-29 DOI: 10.1016/j.ymthe.2025.12.032
Timothy W Yu, Julia Vitarello, Kiran Musunuru, Rebecca C Ahrens-Nicklas, David R Liu, Michelle L Mellion, Fyodor Urnov, Winston Yan, Srinivas Chunduru, David Barrett, Terence R Flotte, Janet Woodcock
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引用次数: 0
A precision gene-engineered B cell medicine producing sustained levels of active factor IX for hemophilia B therapy. 一种精密基因工程B细胞药物产生持续水平的活性因子IX治疗血友病B。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-09-05 DOI: 10.1016/j.ymthe.2025.09.001
Hanlan Liu, Swati Singh, Timothy J Mullen, Caroline Bullock, Sean Keegan, Troy Patterson, Sakshisingh Thakur, Amy Lundberg, Sol Shenker, Ryan Couto, Charuta Yadav, Shamael Dastagir, Lily Li, Wayne Bainter, Ella Liberzon, Connor R Malloy, Cicera R Lazzarotto, Toshiro K Ohsumi, Shalini Chilakala, Huei-Mei Chen, Rashmi Kshirsagar, Anja F Hohmann, Sean P Arlauckas, Adam Lazorchak, Chris Scull, Richard A Morgan

Hemophilia B gene therapy treatments have not addressed the need for predictable, durable, active, and redosable factor IX (FIX). Unlike conventional gene therapy, engineered B cell medicines (BCMs) are durable, redosable, and titratable and thus have the potential to address significant unmet needs in the hemophilia B treatment paradigm. BE-101 is an autologous BCM comprising expanded and differentiated B lymphocyte lineage cells genetically engineered ex vivo to secrete factor IX (FIX)-Padua. CRISPR-Cas9-mediated gene editing at the C-C chemokine receptor type 5 (CCR5) locus was used to facilitate transgene insertion of an adeno-associated virus 6-encoded DNA template via homology-directed repair. Transgene insertion did not alter B cell biology, viability, or differentiation into plasma cells. Appreciable levels of BE-101-derived FIX-Padua were detected within 1 day after IV administration in mice, and steady state was reached within 2 weeks and persisted for over 184 days. Redosing produced an increase in FIX-Padua production close to linear dose proportionality. Comprehensive genotoxicity analysis found no off-target issues of concern. No safety signals were observed in animal tolerability and Good Laboratory Practice toxicology studies. In conclusion, BE-101 produces sustained levels of active FIX-Padua with the ability to engraft without host preconditioning and with the potential for redosing and titratability.

血友病B基因治疗目前还没有解决对可预测、持久、有效和可重复使用的因子IX (FIX)的需求。与传统基因治疗不同,工程B细胞药物(bcm)具有持久性、可重复使用和可滴定性,因此有可能解决血友病B治疗模式中未满足的重大需求。BE-101是一种自体BCM,由扩增和分化的B淋巴细胞系细胞组成,通过基因工程在体外分泌FIX-Padua。利用CRISPR/Cas9介导的C-C趋化因子受体5型位点的基因编辑,通过同源定向修复促进aav6编码DNA模板的转基因插入。转基因插入不会改变B细胞的生物学、生存能力或向浆细胞的分化。小鼠IV给药后1天内检测到be -101衍生的FIX-Padua的显著水平,2周内达到稳定状态,持续时间超过184天。重新给药使FIX-Padua产量的增加接近线性剂量比例。综合遗传毒性分析未发现脱靶问题。在动物耐受性和GLP毒理学研究中未观察到安全信号。综上所述,BE-101产生持续水平的活性FIX-Padua,具有无需宿主预处理即可移植的能力,并且具有重给药和可滴定性的潜力。
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引用次数: 0
A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD. 一种新的多重RNAi疗法同时靶向Hif1a和Hif2a,以对抗两种AMD模型的视网膜变性。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-09-27 DOI: 10.1016/j.ymthe.2025.09.044
Lynn J A Ebner, Cornelia Imsand, Duygu Karademir, Florian Peters, Eva Kiessling, Antonia Fottner, Claudia Matter, Diego S Fajardo, Luca Merolla, Gabriele M Wögenstein, Ioanna Tsioti, Larissa P Govers, Frank Blaser, Isabelle Meneau, Sanford L Boye, Shannon E Boye, Christian Grimm, Marijana Samardzija

Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE) and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single adeno-associated virus, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference (RNAi)-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.

年龄相关的组织变化导致光感受器和视网膜色素上皮(RPE)的氧传递减少,并导致年龄相关性黄斑变性(AMD)的病理。缺氧诱导因子(hfs)在这一过程中的作用使其成为AMD的良好候选治疗靶点。我们开发了一种利用shRNAmir系统的多重双作用疗法,由单个AAV递送,可降低光感受器中Hif1a和RPE中Hif2a的mRNA水平。这种基于RNA干扰的策略显示出强大的治疗效果,在注射后61周的假缺氧和真缺氧两种模型中有效地保存光感受器和RPE。我们的双作用病毒的效果优于单作用病毒仅靶向光感受器中的Hif1a或RPE中的Hif2a。通过靶向一种常见的、保守的疾病途径,这种基因不可知的RNAi疗法显示出在复杂疾病(如AMD)中保护组织免受慢性缺氧损伤的巨大潜力。
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引用次数: 0
Epigenome editing based treatment: Progresses and challenges. 基于表观基因组编辑的治疗:进展和挑战。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-09-01 DOI: 10.1016/j.ymthe.2025.08.047
Luowei Yuan, Yikai Xiong, Yiming Zhang, Shen Gu, Yong Lei

Epigenome editing is emerging as a transformative approach in clinical treatment, enabling precise modifications to gene expression without altering the underlying DNA sequence. The ongoing transition of epigenome editing techniques from foundational research to clinical applications highlights several key strategies. These include targeted DNA methylation/demethylation, histone modification, and transcriptional regulation. These approaches offer the potential for durable and reversible gene expression modulation, paving the way for precisely tailored therapies for genetic and complex diseases. Here, we review pioneering research, technological advancements, granted patents, and clinical trials that have been reported during the past decade. By synthesizing current research and development efforts, this review aims to provide insights into the promising landscape of epigenome editing and its potential to promote therapeutic interventions.

表观基因组编辑正在成为临床治疗中的一种变革性方法,可以在不改变潜在DNA序列的情况下精确修改基因表达。表观基因组编辑技术从基础研究到临床应用的持续转变突出了几个关键策略。这些包括靶向DNA甲基化/去甲基化,组蛋白修饰和转录调控。这些方法提供了持久和可逆的基因表达调节的潜力,为基因和复杂疾病的精确定制治疗铺平了道路。在这里,我们回顾了过去十年中报道的开创性研究、技术进步、授权专利和临床试验。通过综合当前的研究和开发工作,本综述旨在为表观基因组编辑的前景及其促进治疗干预的潜力提供见解。
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引用次数: 0
Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration. 应激诱导的内皮细胞线粒体断裂破坏血液-视网膜屏障的完整性,导致神经变性。
IF 12 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-07 Epub Date: 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.037
Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor for developing glaucoma, induced mitochondrial fragmentation in retinal capillary ECs, accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant-negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.

血管渗漏增加和内皮细胞(EC)功能障碍是神经退行性疾病的主要特征。在这里,我们研究了导致EC失调的机制,并询问EC中线粒体动力学的改变是否会影响血管屏障的完整性和神经变性。我们发现,高眼压是青光眼的一个主要危险因素,可诱导视网膜毛细血管内皮细胞线粒体断裂,并伴有氧化应激增加和超微结构缺陷。对EC线粒体成分的分析显示,在青光眼损伤期间,动力蛋白相关蛋白1 (DRP1)过度激活,DRP1是线粒体分裂的主要调节因子。药理抑制DRP1或ec特异性体内基因传递显性DRP1阴性突变体足以挽救线粒体体积,减少血管渗漏,并增加紧密连接CLDN5 (CLDN5)的表达。我们进一步证明,ec靶向CLDN5基因增强恢复了青光眼小鼠血液-视网膜屏障的完整性,促进了神经元的存活,并改善了光诱发的视觉行为。我们的研究结果表明,保持线粒体稳态和EC功能是增强青光眼神经保护和改善视力的有价值的策略。
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引用次数: 0
cSMRTS for cancer therapeutics 用于癌症治疗的cSMRTS
IF 12.4 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2026-01-06 DOI: 10.1016/j.ymthe.2025.12.054
Sagi Ravid, Inbal Hazan-Halevy, Dan Peer
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引用次数: 0
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Molecular Therapy
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