Molecular Therapy-Methods & Clinical Development最新文献_第7页

Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy 变色性白质营养不良症无症状小鼠模型中静脉注射基因疗法的剂量-反应评估

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-06 DOI: 10.1016/j.omtm.2024.101248

Emilie Audouard, Nicolas Khefif, Charlotte Mansat, Océane Nelcha, Elena-Gaia Banchi, Camille Lupiet, Dominique Farabos, Antonin Lamaziere, Caroline Sevin, Françoise Piguet

{"title":"Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy","authors":"Emilie Audouard, Nicolas Khefif, Charlotte Mansat, Océane Nelcha, Elena-Gaia Banchi, Camille Lupiet, Dominique Farabos, Antonin Lamaziere, Caroline Sevin, Françoise Piguet","doi":"10.1016/j.omtm.2024.101248","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101248","url":null,"abstract":"Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive neurodegenerative disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA), resulting in sulfatide accumulation and subsequent demyelination and neuronal damage within the central and peripheral nervous systems. Three clinical forms of MLD have been described, based on age at symptom onset. The most frequent and severe forms have an early onset, with the disease progressing rapidly toward severe motor and cognitive regression and ultimately premature death. There are currently no approved therapies for most of these early-onset patients once symptoms are present. Thus, it is crucial to develop new approaches to treat symptomatic patients. Here, we proposed a gene therapy approach based on the intravenous delivery of AAVPHP.eB encoding ARSA. MLD mice were treated at 6 months for a dose-response study and at 9 months to assess late-treatment efficacy. Therapeutic efficacy was evaluated 3 or 6 months after injection. We demonstrated a broad transduction in the central nervous system, a complete correction of sulfatide storage, and a significant improvement in neuroinflammation at low dose and late treatment. Taken together, this work establishes a strong rationale for proposing a phase I/II clinical trial in MLD patients.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569379","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

An investigation of the immune epitope properties of adeno-associated virus capsid-derived peptides among hemophilia patients 对血友病患者腺相关病毒壳衍生肽免疫表位特性的调查

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-04-02 DOI: 10.1016/j.omtm.2024.101245

Li Liu, Bingqi Xu, Lingling Chen, Jia Liu, Wei Liu, Feng Xue, Sizhou Feng, Erlie Jiang, Mingzhe Han, Wenwei Shao, Lei Zhang, Xiaolei Pei

{"title":"An investigation of the immune epitope properties of adeno-associated virus capsid-derived peptides among hemophilia patients","authors":"Li Liu, Bingqi Xu, Lingling Chen, Jia Liu, Wei Liu, Feng Xue, Sizhou Feng, Erlie Jiang, Mingzhe Han, Wenwei Shao, Lei Zhang, Xiaolei Pei","doi":"10.1016/j.omtm.2024.101245","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101245","url":null,"abstract":"Adeno-associated virus (AAV) is an optimal gene vector for monogenic disorders. However, neutralizing antibodies (Nabs) against AAV hinder its widespread application in gene therapy. In this study, we biosynthesized peptides recognized by the binding antibodies (Babs) from the sera containing high Nab titers against AAV2. We established four immunological methods to detect immune epitopes of the AAV2-derived peptides, including a Bab assay, Nab assay, B cell receptor (BCR) detecting assay, and immunoglobin-producing B cell enzyme-linked immunosorbent spot (B cell ELISpot) assay. Correlations among the epitopes determined by these four methods were analyzed using the serum samples and peripheral blood mononuclear cells from 89 patients with hemophilia A/B. As decoys, the peptides’ ability to block the Nab of AAV2 particles was assessed using AAV transduction models both and . Overall, we provide insights into AAV2-capsid-derived peptide immune epitopes, involving the Nab, Bab, BCR, and B cell ELISpot assays, offering alternative immunological evaluation approaches and strategies to overcome Nab barriers in AAV-mediated gene therapy.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569378","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

Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model 在大型动物模型中，视网膜下 AAV 释放靶向 VEGFA 的 RNAi- 治疗药物可减少脉络膜新生血管的形成

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-22 DOI: 10.1016/j.omtm.2024.101242

Silja Hansen Haldrup, Bjørn K. Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L. Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J. Corydon

{"title":"Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model","authors":"Silja Hansen Haldrup, Bjørn K. Fabian-Jessing, Thomas Stax Jakobsen, Anna Bøgh Lindholm, Rikke L. Adsersen, Lars Aagaard, Toke Bek, Anne Louise Askou, Thomas J. Corydon","doi":"10.1016/j.omtm.2024.101242","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101242","url":null,"abstract":"Neovascular age-related macular degeneration (nAMD) is a frequent cause of vision loss among the elderly in the Western world. Current disease management with repeated injections of anti-VEGF agents accumulates the risk for adverse events and constitutes a burden for society and the individual patient. Sustained suppression of VEGF using gene therapy is an attractive alternative, which we explored using adeno-associated virus (AAV)-based delivery of novel RNA interference (RNAi) effectors in a porcine model of choroidal neovascularization (CNV). The potency of -targeting, Ago2-dependent short hairpin RNAs placed in pri-microRNA scaffolds (miR-agshRNA) was established and in mice. Subsequently, AAV serotype 8 (AAV2.8) vectors encoding -targeting or irrelevant miR-agshRNAs under the control of a tissue-specific promotor were delivered to the porcine retina via subretinal injection before CNV induction by laser. Notably, -targeting miR-agshRNAs resulted in a significant and sizable reduction of CNV compared with the non-targeting control. We also demonstrated that single-stranded and self-complementary AAV2.8 vectors efficiently transduce porcine retinal pigment epithelium cells but differ in their transduction characteristics and retinal safety. Collectively, our data demonstrated a robust anti-angiogenic effect of -targeting miR-aghsRNAs in a large translational animal model, thereby suggesting AAV-based delivery of anti-VEGFA RNAi therapeutics as a valuable tool for the management of nAMD.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140569733","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

Combining CRISPR/Cas mediated terminal resolution with a novel genetic workflow to achieve high-diversity adenoviral libraries 将 CRISPR/Cas 介导的末端解析与新型遗传学工作流程相结合，实现高多样性腺病毒文库

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-18 DOI: 10.1016/j.omtm.2024.101241

Julian Fischer, Ariana Fedotova, Lena Jaki, Erwan Sallard, Anja Erhardt, Jonas Fuchs, Zsolt Ruzsics

{"title":"Combining CRISPR/Cas mediated terminal resolution with a novel genetic workflow to achieve high-diversity adenoviral libraries","authors":"Julian Fischer, Ariana Fedotova, Lena Jaki, Erwan Sallard, Anja Erhardt, Jonas Fuchs, Zsolt Ruzsics","doi":"10.1016/j.omtm.2024.101241","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101241","url":null,"abstract":"While recombinant Adenoviruses are widely used in both laboratory and medical gene transfer, library-based applications using this vector platform are not readily available. Recently, we developed a new method, the CRISPR/Cas9 mediated terminal resolution aiding high-efficiency rescue of recombinant Adenoviruses from recombinant DNA. Here we report on a genetic workflow that allows construction of BAC-based recombinant Adenoviruses libraries reconstituted using highly efficient terminal resolution. We utilized frequent, pre-existing genomic sequences to allow the insertion of a selection marker, complementing two selected target sites into novel endonuclease recognition sites. In the second step, this selection marker is replaced with a transgene or mutation of interest via Gibson assembly. Our approach does not cause unwanted genomic off-target mutations while providing substantial flexibility for the site and nature of the genetic modification. This new genetic workflow, which we termed half-site directed fragment replacement allows the introduction of >10ˆ6 unique modifications into rAd encoding BACs using laboratory scale methodology. To demonstrate the power of HFR, we rescued barcoded viral vector libraries yielding a diversity of ∼2.5x10ˆ4 unique recombinant Adenoviruses per cmˆ2 of transfected cell culture.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150515","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

Strengthening health systems for access to gene therapy in rare genetic disorders 加强卫生系统，促进罕见遗传疾病的基因治疗

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-13 DOI: 10.1016/j.omtm.2024.101220

Sonal Bhatia, Yann Le Cam, Juan Carrion, Lauren Diamond, Paul Fennessy, Safiyya Gassman, Felix Gutzwiller, Stephen Kagan, Diana Pankevich, Jennifer Young Maloney, Nitin Mahadev, Martin Schulz, Durhane Wong-Rieger, Paolo Morgese

引用次数: 0

AAV-delivered hepato-adrenal cooperativity in steroidogenesis: implications for gene therapy for congenital adrenal hyperplasia 类固醇生成过程中的肝-肾协同作用：先天性肾上腺皮质增生症基因疗法的意义

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-12 DOI: 10.1016/j.omtm.2024.101232

Lara E. Graves, Eva B. van Dijk, Erhua Zhu, Sundar Koyyalamudi, Tiffany Wotton, Dinah Sung, Shubha Srinivasan, Samantha L. Ginn, Ian E. Alexander

{"title":"AAV-delivered hepato-adrenal cooperativity in steroidogenesis: implications for gene therapy for congenital adrenal hyperplasia","authors":"Lara E. Graves, Eva B. van Dijk, Erhua Zhu, Sundar Koyyalamudi, Tiffany Wotton, Dinah Sung, Shubha Srinivasan, Samantha L. Ginn, Ian E. Alexander","doi":"10.1016/j.omtm.2024.101232","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101232","url":null,"abstract":"Despite the availability of life-saving corticosteroids for 70 years, treatment for adrenal insufficiency is not able to recapitulate physiological diurnal cortisol secretion and results in numerous complications. Gene therapy is an attractive possibility for monogenic adrenocortical disorders such as congenital adrenal hyperplasia, however, requires further development of gene transfer/editing technologies and knowledge of the target progenitor cell populations. Vectors based on adeno-associated virus are the leading system for direct gene delivery but have limitations in targeting replicating cell populations such as in the adrenal cortex. One strategy to overcome this technological limitation is to deliver the relevant adrenocortical gene to a currently targetable organ outside of the adrenal cortex. To explore this possibility, we developed a vector encoding human 21-hydroxylase and directed expression to the liver in a mouse model of congenital adrenal hyperplasia. This extra-adrenal expression resulted in reconstitution of the steroidogenic pathway. Aldosterone and renin levels normalised, and corticosterone levels improved sufficiently to reduce adrenal hyperplasia. This strategy could provide an alternative treatment option for monogenic adrenal disorders, particularly for mineralocorticoid defects. These findings also demonstrate, when targeting the adrenal gland, that inadvertent liver transduction should be precluded as it may confound data interpretation.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140156554","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

Producing high-quantity and high-quality recombinant adeno-associated virus by low-cis triple transfection 通过低顺式三重转染技术生产高数量和高质量的重组腺相关病毒

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-12 DOI: 10.1016/j.omtm.2024.101230

Hao Liu, Yue Zhang, Mitchell Yip, Lingzhi Ren, Jialing Liang, Xiupeng Chen, Nan Liu, Ailing Du, Jiaming Wang, Hao Chang, Hyejin Oh, Chen Zhou, Ruxiao Xing, Mengyao Xu, Peiyi Guo, Dominic Gessler, Jun Xie, Phillip WL. Tai, Guangping Gao, Dan Wang

{"title":"Producing high-quantity and high-quality recombinant adeno-associated virus by low-cis triple transfection","authors":"Hao Liu, Yue Zhang, Mitchell Yip, Lingzhi Ren, Jialing Liang, Xiupeng Chen, Nan Liu, Ailing Du, Jiaming Wang, Hao Chang, Hyejin Oh, Chen Zhou, Ruxiao Xing, Mengyao Xu, Peiyi Guo, Dominic Gessler, Jun Xie, Phillip WL. Tai, Guangping Gao, Dan Wang","doi":"10.1016/j.omtm.2024.101230","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101230","url":null,"abstract":"Recombinant adeno-associated virus (rAAV)-based gene therapy is entering clinical and commercial stages at an unprecedented pace. Triple transfection of HEK293 cells is currently the most widely used platform for rAAV manufacturing. Here, we develop low-cis triple transfection that reduces the transgene plasmid usage by 10- to 100-fold, and overcomes several major limitations associated with standard triple transfection. This new method improves packaging of yield-inhibiting transgenes by up to 10-fold, and generates rAAV batches with reduced plasmid backbone contamination that otherwise cannot be eliminated in downstream processing. When tested in mice and compared with rAAV produced by standard triple transfection, low-cis rAAV shows comparable or superior potency, and results in diminished plasmid backbone DNA and RNA persistence in tissue. Mechanistically, low-cis triple transfection relies on the extensive replication of transgene cassette (i.e., ITR-flanked vector DNA) in HEK293 cells during production phase. This cost-effective method can be easily implemented and widely applicable to producing rAAV of high quantity, purity, and potency.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150514","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

Novel AAV variants with improved tropism for human Schwann cells 对人类许旺细胞具有更好趋向性的新型 AAV 变体

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-11 DOI: 10.1016/j.omtm.2024.101234

Matthieu Drouyer, Tak-Ho Chu, Elodie Labit, Florencia Haase, Renina Gale Navarro, Deborah Nazareth, Nicole Rosin, Jessica Merjane, Suzanne Scott, Marti Cabanes-Creus, Adrian Westhaus, Erhua Zhu, Rajiv Midha, Ian E. Alexander, Jeff Biernaskie, Samantha L. Ginn, Leszek Lisowski

{"title":"Novel AAV variants with improved tropism for human Schwann cells","authors":"Matthieu Drouyer, Tak-Ho Chu, Elodie Labit, Florencia Haase, Renina Gale Navarro, Deborah Nazareth, Nicole Rosin, Jessica Merjane, Suzanne Scott, Marti Cabanes-Creus, Adrian Westhaus, Erhua Zhu, Rajiv Midha, Ian E. Alexander, Jeff Biernaskie, Samantha L. Ginn, Leszek Lisowski","doi":"10.1016/j.omtm.2024.101234","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101234","url":null,"abstract":"Gene therapies and associated technologies are transforming biomedical research and enabling novel therapeutic options for patients living with debilitating and incurable genetic disorders. The vector system based on recombinant adeno-associated viral vectors (AAVs) has shown great promise in recent clinical trials for genetic diseases of multiple organs, such as the liver and the nervous system. Despite recent successes toward the development of novel bioengineered AAV variants for improved transduction of primary human tissues and cells, vectors that can efficiently transduce human Schwann cells (hSCs) have yet to be identified. Here, we report the application of the functional transduction-RNA selection method in primary hSCs for the development of bespoke AAV variants for specific and efficient transgene delivery to hSCs. The two identified capsid variants, Pep2hSC1 and Pep2hSC2, show conserved potency for delivery across various , , and models of hSCs. These novel AAV capsids will serve as valuable research tools, forming the basis for therapeutic solutions for both SC-related disorders or peripheral nervous system injury.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140150289","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

Non-canonical capsid engineering highlights new possibilities for AAV vectorology 非典型囊壳工程彰显 AAV 载体学的新可能性

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-06 DOI: 10.1016/j.omtm.2024.101221

Zehan Zhang, John R. Counsell

引用次数: 0

A robust and flexible baculovirus-insect cell system for AAV vector production with improved yield, capsid ratios and potency 用于生产 AAV 向量的稳健而灵活的杆状病毒-昆虫细胞系统，可提高产量、囊壳比率和效力

IF 4.7 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-03-04 DOI: 10.1016/j.omtm.2024.101228

Yoko Marwidi, Hoang-Oanh B. Nguyen, David Santos, Tenzin Wangzor, Sumita Bhardwaj, Gabriel Ernie, Gregg Prawdzik, Garrett Lew, David Shivak, Michael Trias, Jada Padilla, Hung Tran, Kathleen Meyer, Richard Surosky, Alex Michael Ward

{"title":"A robust and flexible baculovirus-insect cell system for AAV vector production with improved yield, capsid ratios and potency","authors":"Yoko Marwidi, Hoang-Oanh B. Nguyen, David Santos, Tenzin Wangzor, Sumita Bhardwaj, Gabriel Ernie, Gregg Prawdzik, Garrett Lew, David Shivak, Michael Trias, Jada Padilla, Hung Tran, Kathleen Meyer, Richard Surosky, Alex Michael Ward","doi":"10.1016/j.omtm.2024.101228","DOIUrl":"https://doi.org/10.1016/j.omtm.2024.101228","url":null,"abstract":"Manufacturing of adeno-associated viruses (AAV) for gene and cell therapy applications has increased significantly and spurred development of improved mammalian and insect cell-based production systems. We developed a baculovirus-based insect cell production system—the SGMO Helper—with a novel gene architecture and greater flexibility to modulate the expression level and content of individual Rep and Cap proteins. In addition, we incorporated modifications to the AAV6 capsid sequence that improves yield, capsid integrity, and potency. Production of recombinant AAV 6 (rAAV6) using the SGMO Helper had improved yields compared to the Bac-RepCap helper from the Kotin lab. SGMO Helper-derived rAAV6 is resistant to a previously described proteolytic cleavage unique to baculovirus-insect cell production systems and has improved capsid ratios and potency, and , compared with rAAV6 produced using Bac-RepCap. Next-generation sequencing sequence analysis demonstrated that the SGMO Helper is stable over six serial passages and rAAV6 capsids contain comparable amounts of non-vector genome DNA as rAAV6 produced using Bac-RepCap. AAV production using the SGMO Helper is scalable using bioreactors and has improved yield, capsid ratio, and potency. Our studies demonstrate that the SGMO Helper is an improved platform for AAV manufacturing to enable delivery of cutting-edge gene and cell therapies.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097681","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