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Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen presenting cells. 利用 mRNA 电穿孔抗原递呈细胞,将特异性 T 细胞扩增到 SARS-CoV-2 的低突变区。
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-22 DOI: 10.1016/j.omtm.2024.101192
Elizabeth Ogando-Rivas, Paul Castillo, Changlin Yang, Vrunda Trivedi, Dingpeng Zhang, Fernanda Pohl-Guimarães, Ruixuan Liu, Arnav Barpujari, Kate M. Candelario, Hector Mendez-Gomez, Elias J. Sayour, Duane A. Mitchell

The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRβ repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID19 vaccines with potential protection across new variants that have conserved genetic regions.

COVID-19 大流行已造成全球约 700 万人死亡。目前已开发出预防性疫苗,包括基于 Spike gp mRNA 的疫苗,可为免疫功能正常的患者提供保护。然而,原发性免疫缺陷患者、癌症患者或造血干细胞移植受者无法对目前的疫苗方法产生强有力的免疫反应。我们建议利用电穿孔了全长 SARS-CoV-2 结构蛋白编码 mRNA 的循环人类抗原呈递细胞,以 SARS-CoV-2 结构抗原(即尖峰 gp、膜、核壳和包膜)为靶标,激活和扩增特异性 T 细胞。根据抗原再刺激时 Th1 型细胞因子和细胞溶解酶的分泌情况,我们能够在未接触过 SARS-CoV-2 的未接种过疫苗的健康供体(HDs)中,在随后的 3 次刺激后产生高达 70% 的 SARS-CoV-2 特异性 T 细胞,在康复患者(RPs)中,在 2 次刺激后产生 100% 的 T 细胞。通过 SARS-CoV-2 特异性 TCRβ 反应谱分析,在 HDs 和 RPs 中发现了针对 Spike gp 衍生低突变区的特异性 T 细胞,尽管病毒基因组发生了进化。因此,我们证明了装载 SARS-CoV-2 mRNA 的抗原呈递细胞能有效激活和扩增 COVID19 特异性 T 细胞。对于那些无法对目前的 COVID19 疫苗产生适应性免疫反应的患者来说,这种方法是一种替代方案,可对基因区域保持不变的新变体提供潜在保护。
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引用次数: 0
AAV8 Gene Therapy Reverses Cardiac Pathology and Prevents Early Mortality in a Mouse Model of Friedreich’s Ataxia AAV8 基因疗法可逆转弗里德里希共济失调小鼠模型的心脏病理变化并防止早期死亡
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-22 DOI: 10.1016/j.omtm.2024.101193
Joshua C. Chang, Molly R. Ryan, Marie C. Stark, Su Liu, Pravinkumar Purushothaman, Fria Bolan, Caitlin A. Johnson, Mark Champe, Hui Meng, Michael W. Lawlor, Sarah Halawani, Lucie V. Ngaba, David R. Lynch, Crystal Davis, Elena Gonzalo-Gil, Cathleen Lutz, Fabrizia Urbinati, Bala Medicherla, Carlos Fonck

Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein, frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of FRDA’s cardiac phenotype was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has a FXN gene ablation that prevents frataxin expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN gene under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks post dose. Frataxin protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild-type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

弗里德雷希共济失调症(FRDA)是一种常染色体隐性遗传疾病,主要是由于双倍性 GAA 重复扩增导致线粒体蛋白 frataxin(FXN)表达减少所致。FRDA的特征是进行性神经变性,许多患者会发展为心肌病,进而导致心力衰竭和死亡。研究人员利用含有 FXN 基因编码序列的腺相关病毒载体(AAV8),在 FRDA 小鼠模型中研究了逆转或预防 FRDA 心脏表型进展的可能性。Fxnflox/null::MCK-Cre条件性基因敲除小鼠(FXN-MCK)的FXN基因消减阻止了frataxin在心肌和骨骼肌中的表达,导致心功能不全、体重减轻和发病。FXN-MCK 小鼠接受了一次含有人(hFXN)或小鼠(mFXN)FXN 基因的 AAV8 载体静脉注射,该载体受磷酸甘油激酶启动子控制。与经药物治疗的 FXN-MCK 对照组小鼠相比,经 AAV 治疗的 FXN-MCK 小鼠体重增加、心脏功能障碍逆转、存活率提高,且在服药后 12 周内心脏或肝脏无明显毒性。在心脏组织中检测到的 Frataxin 蛋白表达呈剂量依赖性,其在整个心脏中的广泛分布与野生型相似,但斑点更多。这些结果支持用基于 AAV8 的方法治疗 FRDA 相关心肌病。
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引用次数: 0
High-titer manufacturing of SARS-CoV-2 spike-pseudotyped VSV in stirred-tank bioreactors 在搅拌罐生物反应器中制造高滴度 SARS-CoV-2 尖峰伪型 VSV
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-17 DOI: 10.1016/j.omtm.2024.101189
Hayley M. Todesco, Chris Gafuik, Cini M. John, Erin L. Roberts, Breanna S. Borys, Alexis Pawluk, Michael S. Kallos, Kyle G. Potts, Douglas J. Mahoney

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic highlighted the importance of vaccine innovation in public health. Hundreds of vaccines built on numerous technology platforms were rapidly developed against SARS-CoV-2 since 2020. Like all vaccine platforms, an important bottleneck to viral-vectored vaccine development is manufacturing. Here, we describe a scalable manufacturing protocol for replication-competent SARS-CoV-2 Spike-pseudotyped Vesicular Stomatitis Virus (S-VSV)-vectored vaccines using Vero cells grown on microcarriers in a stirred-tank bioreactor. Using Cytodex 1 microcarriers over 6 days of fed-batch culture, Vero cells grew to a density of 3.95 + 0.42 ×106 cells/mL in 1 L stirred-tank bioreactors. Ancestral strain S-VSV reached a peak titer of 2.05 + 0.58 ×108 plaque-forming units (pfu)/mL at 3 days post-infection. When compared to growth in plate-based cultures this was a 29-fold increase in virus production, meaning a 1 L bioreactor produces the same amount of virus as 1284 15cm plates. Additionally, the omicron BA.1 S-VSV reached a peak titer of 5.58 + 0.35 ×106 pfu/mL. Quality control testing showed plate- and bioreactor-produced S-VSV had similar particle-to-pfu ratios and elicited comparable levels of neutralizing antibodies in immunized hamsters. This method should enhance preclinical and clinical development of pseudotyped VSV-vectored vaccines in future pandemics.

严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)大流行凸显了疫苗创新在公共卫生领域的重要性。自 2020 年以来,针对 SARS-CoV-2 快速开发了数百种建立在众多技术平台上的疫苗。与所有疫苗平台一样,病毒载体疫苗开发的一个重要瓶颈是生产。在此,我们介绍了一种可扩展的 SARS-CoV-2 Spike 伪型水泡性口炎病毒(S-VSV)载体疫苗制造方案,该方案使用在搅拌罐生物反应器中微载体上生长的 Vero 细胞。使用 Cytodex 1 微载体进行为期 6 天的分批进行培养,Vero 细胞在 1 升搅拌罐生物反应器中的生长密度达到 3.95 + 0.42 ×106 cells/mL。祖先菌株 S-VSV 在感染后 3 天达到峰值滴度 2.05 + 0.58 ×108 plaque-forming units (pfu)/mL。与平板培养相比,病毒产量增加了 29 倍,这意味着 1 升生物反应器产生的病毒量与 1284 块 15 厘米平板产生的病毒量相同。此外,ocmicron BA.1 S-VSV 的峰值滴度为 5.58 + 0.35 ×106 pfu/mL。质量控制测试表明,平板和生物反应器生产的 S-VSV 粒子与 pfu 的比率相似,在免疫仓鼠体内激发的中和抗体水平相当。在未来的大流行病中,这种方法将有助于伪型 VSV 病毒载体疫苗的临床前和临床开发。
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引用次数: 0
Mannose-coupled AAV2: a second generation AAV vector for increased retinal gene therapy efficiency 甘露糖偶联 AAV2:提高视网膜基因治疗效率的第二代 AAV 载体
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-17 DOI: 10.1016/j.omtm.2024.101187
Mathieu Mével, Virginie Pichard, Mohammed Bouzelha, Dimitri Alvarez-Dorta, Pierre-Alban Lalys, Nathalie Provost, Marine Allais, Alexandra Mendes, Elodie Landagaray, Jean-Baptiste Ducloyer, Estelle Toublanc, Anne Galy, Nicole Brument, Gaëlle M. Lefevre, Sébastien G. Gouin, Carolina Isiegas, Guylène Le Meur, Thérèse Cronin, Caroline Le Guiner, Michel Weber, Oumeya Adjali

Inherited retinal diseases are a leading and untreatable cause of blindness and are therefore candidate diseases for gene therapy. Recombinant vectors derived from adeno-associated virus (rAAV) are currently the most promising vehicles for in vivo therapeutic gene delivery to the retina. However, there is a need for novel AAV-based vectors with greater efficacy for ophthalmic applications, as underscored by recent reports of dose-related inflammatory responses in clinical trials of rAAV-based ocular gene therapies. Improved therapeutic efficacy of vectors would allow for decreases in the dose delivered, with consequent reductions in inflammatory reactions. Here, we describe the development of new rAAV vectors using bioconjugation chemistry to modify the rAAV capsid, thereby improving the therapeutic index. Covalent coupling of a mannose ligand, via the formation of a thiourea bond, to the amino groups of the rAAV capsid significantly increases vector transduction efficiency of both rat and nonhuman primate retinas. These optimized rAAV vectors have important implications for the treatment of a wide range of retinal diseases.

遗传性视网膜疾病是导致失明的主要原因之一,而且无法治疗,因此是基因治疗的候选疾病。源自腺相关病毒(rAAV)的重组载体是目前最有希望向视网膜体内输送治疗基因的载体。然而,最近有报道称,在基于 rAAV 的眼部基因疗法的临床试验中,出现了与剂量相关的炎症反应,这说明眼科应用需要疗效更好的新型 AAV 载体。提高载体的疗效可以降低给药剂量,从而减少炎症反应。在此,我们介绍了新型 rAAV 载体的开发过程,利用生物共轭化学修饰了 rAAV 的囊壳,从而提高了治疗指数。通过形成硫脲键,将甘露糖配体与 rAAV 病毒壳的氨基进行共价偶联,大大提高了大鼠和非人灵长类视网膜的载体转导效率。这些优化的 rAAV 载体对治疗多种视网膜疾病具有重要意义。
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引用次数: 0
Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia 在半乳糖血症小鼠模型中,将全身半乳糖氧化作为一种稳健的功能检测方法来评估基于基因的疗法的疗效
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-17 DOI: 10.1016/j.omtm.2024.101191
Bijina Balakrishnan, Xinhua Yan, Marshall D. McCue, Olivia Bellagamba, Aaron Guo, Felicity Winkler, Jason Thall, Lisa Crawford, Rain Dimen, Sara Chen, Sean McEnaney, Yiman Wu, Mike Zimmer, Joe Sarkis, Paolo GV. Martini, Patrick F. Finn, Kent Lai

Despite the implementation of life-saving newborn screening programs and a galactose-restricted diet, many patients with Classic Galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which not only decreased galactose-1 phosphate (gal-1P) in the liver, but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, non-invasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of Galactosemia. While our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that target the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.

尽管实施了挽救生命的新生儿筛查计划和限制半乳糖的饮食,但许多典型半乳糖血症患者仍会出现长期衰弱的神经功能障碍和原发性卵巢功能不全。此前,我们曾发现,给主要表达于 GalT 基因诱导的小鼠肝脏中的人类 GALT mRNA 会增强肝脏 GALT 活性的表达,这不仅会降低肝脏中的半乳糖-1 磷酸酯(gal-1P),还会降低外周组织中的半乳糖-1 磷酸酯(gal-1P)。由于每个外周组织都需要不同的方法来检测生物标记物和/或 GALT 的效果,这就凸显了采用其他策略来评估疗法整体影响的必要性。在这项研究中,我们确定了全身半乳糖氧化(WBGO)作为一种稳健、非侵入性和特异性的方法来评估两种基于基因的实验性疗法的体内药代动力学和药效学参数,这些疗法旨在恢复半乳糖血症小鼠模型中 GALT 的活性。我们的结果表明了 AAVrh10 介导的 GALT 基因转移的持久疗效,同时我们发现主要针对肝脏的 GALT mRNA 疗法足以维持 WBGO。后者对设计新型靶向疗法以确保最佳疗效和安全性具有重要意义。
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引用次数: 0
Extracellular vesicle depletion and UGCG overexpression mitigate the cell density effect in HEK293 cell culture transfection. 在 HEK293 细胞培养转染过程中,细胞外囊泡耗竭和 UGCG 过表达可减轻细胞密度效应。
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-17 DOI: 10.1016/j.omtm.2024.101190
Pol Pérez-Rubio, Jesús Lavado-García, Laia Bosch-Molist, Elianet Lorenzo Romero, Laura Cervera, Francesc Gòdia

The hitherto unexplained reduction of cell-specific productivity in transient gene expression (TGE) at high cell density (HCD) is known as the cell density effect (CDE). It currently represents a major challenge in TGE-based bioprocess intensification. This phenomenon has been largely reported but the molecular principles governing it are still unclear. The CDE is currently understood to be caused by the combination of an unknown inhibitory compounds in the extracellular medium and an uncharacterized cellular change at HCD. This study investigates the role of extracellular vesicles (EVs) as extracellular inhibitors for transfection through the production of HIV-1 Gag virus-like particles (VLPs) via transient transfection in HEK293 cells. EV-depletion from the extracellular medium restored transfection efficiency in conditions suffering from the CDE, also enhancing VLP budding and improving production by 60%. Moreover, an alteration in endosomal formation was observed at HCD, sequestering polyplexes and preventing transfection. Overexpression of UGCG enzyme removed intracellular polyplex sequestration, improving transfection efficiency. Combining EV-depletion and UGCG overexpression improved transfection efficiency by ∼45% at 12x106 cells/mL. These results suggest that the interaction between polyplexes and extracelluar and intracellular vesicles plays a crutial role in the CDE, providing insights for the development of strategies to mitigate its impact.

在高细胞密度(HCD)条件下,瞬时基因表达(TGE)中细胞特异性生产率的降低迄今尚未得到解释,这种现象被称为细胞密度效应(CDE)。目前,它是基于瞬时基因表达的生物工艺强化过程中的一大挑战。这一现象已有大量报道,但其分子原理仍不清楚。目前的理解是,CDE 是由细胞外介质中未知的抑制性化合物和 HCD 时未定性的细胞变化共同作用造成的。本研究通过在 HEK293 细胞中瞬时转染 HIV-1 Gag 病毒样颗粒(VLPs),研究了细胞外囊泡(EVs)作为细胞外抑制剂对转染的作用。从细胞外培养基中去除 EV 可恢复 CDE 条件下的转染效率,还能增强 VLP 的萌发并将产量提高 60%。此外,在 HCD 观察到内质体形成发生了改变,封存了多聚体,阻碍了转染。过表达 UGCG 酶可消除细胞内的多聚体封存,提高转染效率。在 12x106 个细胞/毫升的转染条件下,EV 去除和 UGCG 过度表达相结合可将转染效率提高 45%。这些结果表明,多聚体与细胞外和细胞内囊泡之间的相互作用在CDE中起着关键作用,为制定减轻CDE影响的策略提供了启示。
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引用次数: 0
Recombinant AAV Genome Size Effect on Viral Vector Production, Purification, and Thermostability 重组 AAV 基因组大小对病毒载体生产、纯化和耐热性的影响
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-17 DOI: 10.1016/j.omtm.2024.101188
Nermin Ibreljic, Benjamin E. Draper, Carl W. Lawton

Adeno-associated virus (AAV) has shown great promise as a viral vector for gene therapy in clinical applications. This work studied the effect of the genome size on AAV production, purification, and thermostability by producing AAV2-GFP using suspension adapted HEK293 cells via triple transfection using AAV plasmids containing the same green fluorescent protein (GFP) transgene with DNA stuffers for variable size AAV genomes consisting of 1.9, 3.4, and 4.9 kb (ITR to ITR). Production was performed at the small and large shake flask scales and the results showed that the 4.9 kb GFP genome had significantly reduced encapsidation compared to other genomes. The large shake flask productions were purified by AEX chromatography and the results suggest that the triple transfection condition significantly impacts the AEX retention time and resolution between the full and empty capsid peaks. Charge detection mass spectrometry (CD-MS) was performed on all AEX full capsid peak samples showing a wide distribution of empty, partial, full length, and co-packaged DNA in the capsids. The AEX purified samples were then analyzed by differential scanning fluorimetry (DSF) and the results suggest that sample formulation may improve the thermostability of AAV genome ejection melting temperature regardless of the packaged genome content.

腺相关病毒(AAV)作为基因治疗的病毒载体在临床应用中显示出巨大的前景。这项研究利用悬浮适配的 HEK293 细胞,通过使用含有相同绿色荧光蛋白(GFP)转基因的 AAV 质粒进行三重转染,生产 AAV2-GFP,基因组大小对 AAV 生产、纯化和热稳定性的影响,AAV 基因组由 1.9、3.4 和 4.9 kb(ITR 到 ITR)组成。结果表明,与其他基因组相比,4.9 kb GFP 基因组的包被率明显降低。采用 AEX 色谱法纯化了大型摇瓶生产的产品,结果表明,三重转染条件对 AEX 保留时间以及全囊壳峰和空囊壳峰之间的分辨率有显著影响。对所有 AEX 全包囊峰样品进行了电荷检测质谱分析(CD-MS),结果显示包囊中广泛分布着空 DNA、部分 DNA、全长 DNA 和共包装 DNA。然后用差示扫描荧光定量法(DSF)对 AEX 纯化样品进行了分析,结果表明,无论包装的基因组含量如何,样品配方都可以提高 AAV 基因组弹射熔解温度的恒温性。
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引用次数: 0
New perspectives for gene therapy of the X-linked form of Charcot-Marie-Tooth disease X连锁型夏科-玛丽-牙病基因疗法的新前景
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-12 DOI: 10.1016/j.omtm.2023.101184
Rafael Balada Caballé, Mario Bortolozzi
Abstract not available
无摘要
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引用次数: 0
Can mitochondria brown the lower-limb adipocytes? 线粒体能使下肢脂肪细胞变褐吗?
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-05 DOI: 10.1016/j.omtm.2023.101181
Ilias P. Doulamis, Aspasia Tzani
Abstract not available
无摘要
{"title":"Can mitochondria brown the lower-limb adipocytes?","authors":"Ilias P. Doulamis, Aspasia Tzani","doi":"10.1016/j.omtm.2023.101181","DOIUrl":"https://doi.org/10.1016/j.omtm.2023.101181","url":null,"abstract":"Abstract not available","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139376428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic surgery for a cystic fibrosis-causing splicing mutation 针对导致囊性纤维化的剪接突变的基因手术
IF 4.7 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-02 DOI: 10.1016/j.omtm.2023.101177
Mattijs Bulcaen, Marianne S. Carlon
Abstract not available
无摘要
{"title":"Genetic surgery for a cystic fibrosis-causing splicing mutation","authors":"Mattijs Bulcaen, Marianne S. Carlon","doi":"10.1016/j.omtm.2023.101177","DOIUrl":"https://doi.org/10.1016/j.omtm.2023.101177","url":null,"abstract":"Abstract not available","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139094279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Molecular Therapy-Methods & Clinical Development
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