Molecular Therapy-Methods & Clinical Development最新文献

Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions. 优化罕见病基因治疗的监管框架：挑战和解决方案。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-12-05 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101386

Diane Berry, Kate Donigan, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs

{"title":"Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.","authors":"Diane Berry, Kate Donigan, Lisa Kahlman, James Long, Christina Markus, Caitlin K McCombs","doi":"10.1016/j.omtm.2024.101386","DOIUrl":"10.1016/j.omtm.2024.101386","url":null,"abstract":"The advent of genetic medicines and advanced diagnostics has revolutionized the treatment landscape for rare diseases and, with over 10,000 identified conditions affecting millions globally, has the potential to improve many lives. Despite this progress, only 5% of rare diseases have FDA-approved therapies, highlighting a significant unmet need. This article examines the critical need for optimizing the regulatory environment to support the development and approval of gene therapies for rare and ultrarare diseases, which often face unique challenges due to their complexity in the midst of a rapidly evolving field. Key issues discussed include the mismatch between traditional regulatory paradigms and the nature of gene therapies, the need for innovative clinical trial designs, and the importance of flexible manufacturing processes. The article proposes targeted reforms to align regulatory frameworks with the needs of patients with rare diseases and the pace of science, emphasizing the value of a holistic evidence approach, platform technologies, and iterative manufacturing evaluations. By addressing these challenges, we can accelerate the development of life-changing therapies in order to realize the opportunity to provide treatments to patients with rare genetic disorders in their lifetime.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101386"},"PeriodicalIF":4.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thank you to our 2024 reviewers. 感谢我们的 2024 评论员。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-12-02 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101387

引用次数: 0

Determining recombinant AAV capsid extracellular and intracellular biodistribution by dual radioisotope labeling. 双放射性同位素标记法测定重组AAV衣壳细胞内外生物分布。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-21 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101373

Randy J Chandler

引用次数: 0

Size-exclusion chromatography as a multi-attribute method for process and product characterization of adeno-associated virus. 尺寸排阻色谱法作为一种多属性方法，用于表征腺相关病毒的过程和产品特征。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-19 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101382

Sri Hari Raju Mulagapati, Arun Parupudi, Tomasz Witkos, Nick Bond, Xiaoyu Chen, Thomas Linke, Guoling Xi, Albert Ethan Schmelzer, Wei Xu

{"title":"Size-exclusion chromatography as a multi-attribute method for process and product characterization of adeno-associated virus.","authors":"Sri Hari Raju Mulagapati, Arun Parupudi, Tomasz Witkos, Nick Bond, Xiaoyu Chen, Thomas Linke, Guoling Xi, Albert Ethan Schmelzer, Wei Xu","doi":"10.1016/j.omtm.2024.101382","DOIUrl":"10.1016/j.omtm.2024.101382","url":null,"abstract":"Adeno-associated viruses (AAVs) have recently emerged as a leading platform for gene therapy. Due to the complex manufacturing process and structural features of AAVs, extensive process and product characterization studies are required to better understand product quality and batch-to-batch variability. It is, therefore, critical to develop a fast and reliable analytical method to monitor different product quality attributes (PQAs) of AAVs. In this study, we developed a multiple-attribute monitoring (MAM) method for the characterization of AAV PQAs. The MAM method was developed using the separation capability of size-exclusion chromatography (SEC) in connection with multiple in-line detectors: ultraviolet (UV), fluorescence (FLD), multi-angle light scattering (MALS), and refractive index (RI). We demonstrate that our SEC-based MAM method can be used to measure different PQAs, including genome and capsid titer, purity, aggregation, and full/empty capsid ratios in a single assay. Our SEC-based MAM method achieves similar results when compared side by side with orthogonal, individual assays such as quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and anion-exchange chromatography (AEX). Moreover, here we demonstrate that a simple, label-free, cost-effective, minimum sample requirement, and a high-throughput method can be applied to support process development, product characterization, release, and stability testing.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101382"},"PeriodicalIF":4.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptomics-informed pharmacology identifies epigenetic and cell cycle regulators that enhance AAV production. 转录组学告知药理学鉴定表观遗传和细胞周期调节增强AAV的生产。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-18 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101384

Joshua Tworig, Francis Grafton, Kaylin Fisher, Markus Hörer, Christopher A Reid, Mohammad A Mandegar

{"title":"Transcriptomics-informed pharmacology identifies epigenetic and cell cycle regulators that enhance AAV production.","authors":"Joshua Tworig, Francis Grafton, Kaylin Fisher, Markus Hörer, Christopher A Reid, Mohammad A Mandegar","doi":"10.1016/j.omtm.2024.101384","DOIUrl":"10.1016/j.omtm.2024.101384","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) is a widely used viral vector for gene therapy. However, these vectors have limited availability due to manufacturing challenges with productivity and quality. These challenges can be addressed by better understanding the mechanisms that influence cellular responses during rAAV production. In this study, we aimed to identify targets that may enhance rAAV production using transcriptomic analyses of five cell lines with variable capacities for rAAV production. Using an intersectional approach, we measured the transcriptional responses of these cells during rAAV production and compared transcriptional profiles between high and base producers to identify possible targets for enhancing production. During rAAV production, we found transcriptional differences in cell cycle and nucleosome components contributed to proliferative capacity and DNA replication. We also saw upregulation of several core functions, including transcription, stress response, and Golgi and endoplasmic reticulum organization. Conversely, we saw consistent downregulation of other factors, including inhibitors of DNA-binding proteins and mitochondrial components. With a drug-connectivity analysis, we identified five classes of drugs that were predicted to enhance rAAV production. We also validated the efficacy of histone deacetylase and microtubule inhibitors. Our data uncover novel and previously identified pathways that may enhance rAAV production and quality to expand availability of rAAV for gene therapies.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101384"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142839660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quantitative proteomic analysis of residual host cell protein retention across adeno-associated virus affinity chromatography. 通过腺相关病毒亲和层析对宿主细胞蛋白残留进行定量蛋白质组学分析。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-18 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101383

Thomas M Leibiger, Lie Min, Kelvin H Lee

{"title":"Quantitative proteomic analysis of residual host cell protein retention across adeno-associated virus affinity chromatography.","authors":"Thomas M Leibiger, Lie Min, Kelvin H Lee","doi":"10.1016/j.omtm.2024.101383","DOIUrl":"10.1016/j.omtm.2024.101383","url":null,"abstract":"To better understand host cell protein (HCP) retention in adeno-associated virus (AAV) downstream processes, sequential window acquisition of all theoretical fragment ion mass spectra (SWATH-MS) was used to quantitatively profile residual HCPs for four AAV serotypes (AAV2, -5, -8, and -9) produced with HEK293 cells and purified using POROS CaptureSelect AAVX affinity chromatography. A broad range of residual HCPs were detected in affinity eluates after purification (N total = 2,746), and HCP profiles showed universally present species (N universal = 1,117) and species unique to one or more AAV serotype. SWATH-MS revealed that HCP persistence was dominated by high-abundance conserved species (HACS), which appeared across all serotype conditions studied. Due to the notable contribution of these species to overall residual HCP levels, physical and functional characteristics of HACS were examined to determine trends that coincide with persistence. Subnetwork interaction mapping and Gene Ontology function enrichment analysis revealed extensive physical interactions between these proteins and significant enrichment for biological processes, molecular functions, and reactome pathways related to protein folding, nucleic acid binding, and cellular stress. The abundant and conserved nature of these HCPs and their functions offers a new perspective for mechanistic evaluations of impurity retention for AAV downstream processes.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101383"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells. 高亲和力嵌合抗原受体信号诱导人类调节性 T 细胞的炎症程序。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-18 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101385

Russell W Cochrane, Rob A Robino, Bryan Granger, Eva Allen, Silvia Vaena, Martin J Romeo, Aguirre A de Cubas, Stefano Berto, Leonardo M R Ferreira

{"title":"High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells.","authors":"Russell W Cochrane, Rob A Robino, Bryan Granger, Eva Allen, Silvia Vaena, Martin J Romeo, Aguirre A de Cubas, Stefano Berto, Leonardo M R Ferreira","doi":"10.1016/j.omtm.2024.101385","DOIUrl":"10.1016/j.omtm.2024.101385","url":null,"abstract":"Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28-activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3+ CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101385"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting. 编码膜锚定SARS-CoV-2突变体rbd的mRNA疫苗可诱导强烈的体液反应，并可克服免疫印迹。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-15 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101380

Hareth A Al-Wassiti, Stewart A Fabb, Samantha L Grimley, Ruby Kochappan, Joan K Ho, Chinn Yi Wong, Chee Wah Tan, Thomas J Payne, Asuka Takanashi, Chee Leng Lee, Rekha Shandre Mugan, Horatio Sicilia, Serena L Y Teo, Julie McAuley, Paula Ellenberg, James P Cooney, Kathryn C Davidson, Richard Bowen, Marc Pellegrini, Steven Rockman, Dale I Godfrey, Terry M Nolan, Lin-Fa Wang, Georgia Deliyannis, Damian F J Purcell, Colin W Pouton

{"title":"mRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting.","authors":"Hareth A Al-Wassiti, Stewart A Fabb, Samantha L Grimley, Ruby Kochappan, Joan K Ho, Chinn Yi Wong, Chee Wah Tan, Thomas J Payne, Asuka Takanashi, Chee Leng Lee, Rekha Shandre Mugan, Horatio Sicilia, Serena L Y Teo, Julie McAuley, Paula Ellenberg, James P Cooney, Kathryn C Davidson, Richard Bowen, Marc Pellegrini, Steven Rockman, Dale I Godfrey, Terry M Nolan, Lin-Fa Wang, Georgia Deliyannis, Damian F J Purcell, Colin W Pouton","doi":"10.1016/j.omtm.2024.101380","DOIUrl":"10.1016/j.omtm.2024.101380","url":null,"abstract":"We investigated mRNA vaccines encoding a membrane-anchored receptor-binding domain (RBD), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail fragments of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In naive mice, RBD-TM mRNA vaccines against SARS-CoV-2 variants induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays revealed broad neutralizing activity against a range of variant RBDs. In the setting of a heterologous boost, against the background of exposure to ancestral whole-spike vaccines, sVNT studies suggested that BA.1 and BA.5 RBD-TM vaccines had the potential to overcome the detrimental effects of immune imprinting. A subsequent heterologous boost study using XBB.1.5 booster vaccines was evaluated using both sVNT and authentic virus neutralization. Geometric mean XBB.1.5 neutralization values after third-dose RBD-TM or whole-spike XBB.1.5 booster vaccines were compared with those after a third dose of ancestral spike booster vaccine. Fold-improvement over ancestral vaccine was just 1.3 for the whole-spike XBB.1.5 vaccine, similar to data published using human serum samples. In contrast, the fold-improvement achieved by the RBD-TM XBB.1.5 vaccine was 16.3, indicating that the RBD-TM vaccine induced the production of antibodies that neutralize the XBB.1.5 variant despite previous exposure to ancestral spike protein.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101380"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Implementing a robust platform analytical procedure for measuring adeno-associated virus vector genome titer. 实施稳健的平台分析程序，测量腺相关病毒载体基因组滴度。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-15 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101381

Thomas W Powers, Courtney D K Sloan, Don Stano, Brad Evans, Kang Liu, Shawn Mariani, Jessica A Campbell, Thomas F Lerch, Jim J Mo

{"title":"Implementing a robust platform analytical procedure for measuring adeno-associated virus vector genome titer.","authors":"Thomas W Powers, Courtney D K Sloan, Don Stano, Brad Evans, Kang Liu, Shawn Mariani, Jessica A Campbell, Thomas F Lerch, Jim J Mo","doi":"10.1016/j.omtm.2024.101381","DOIUrl":"10.1016/j.omtm.2024.101381","url":null,"abstract":"The vector genome (vg) titer measurement, which is used to control patient dosing and ensure control over drug product manufacturing, is essential for the development of recombinant adeno-associated virus (AAV) gene therapy products. While qPCR and droplet digital PCR technologies are commonly implemented for measuring vg titer, chromatographic techniques with UV detectors represent promising future approaches, in line with traditional biotherapeutics. Here, we introduce a novel vg titer measurement approach using size-exclusion high-performance liquid chromatography with UV detection, which achieves excellent method precision (<2% relative SD), demonstrates linearity across a range of concentrations and varied particle content, is stability indicating, and can be bridged with existing vg titer methods. As there is no bias between this procedure and existing vg titer procedures, such as qPCR, this method can be implemented even at late stages during pharmaceutical development. The procedure was demonstrated to be applicable across serotypes and transgenes, enabling the approach to be used as a platform method for AAV. Given the method performance and criticality of vg titer measurements for AAV, this approach represents a beneficial technology for AAV therapeutics.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101381"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts. 脊髓性肌萎缩成纤维细胞对SMN2剪接修饰治疗的患者特异性反应

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-11-13 eCollection Date: 2024-12-12 DOI: 10.1016/j.omtm.2024.101379

Ilaria Signoria, Maria M Zwartkruis, Lotte Geerlofs, Elena Perenthaler, Kiterie M E Faller, Rachel James, Harriet McHale-Owen, Jared W Green, Joris Kortooms, Sophie H Snellen, Fay-Lynn Asselman, Thomas H Gillingwater, Gabriella Viero, Renske I Wadman, W Ludo van der Pol, Ewout J N Groen

{"title":"Patient-specific responses to SMN2 splice-modifying treatments in spinal muscular atrophy fibroblasts.","authors":"Ilaria Signoria, Maria M Zwartkruis, Lotte Geerlofs, Elena Perenthaler, Kiterie M E Faller, Rachel James, Harriet McHale-Owen, Jared W Green, Joris Kortooms, Sophie H Snellen, Fay-Lynn Asselman, Thomas H Gillingwater, Gabriella Viero, Renske I Wadman, W Ludo van der Pol, Ewout J N Groen","doi":"10.1016/j.omtm.2024.101379","DOIUrl":"10.1016/j.omtm.2024.101379","url":null,"abstract":"The availability of three therapies for the neuromuscular disease spinal muscular atrophy (SMA) highlights the need to match patients to the optimal treatment. Two of these treatments (nusinersen and risdiplam) target splicing of SMN2, but treatment outcomes vary from patient to patient. An incomplete understanding of the complex interactions among SMA genetics, SMN protein and mRNA levels, and gene-targeting treatments, limits our ability to explain this variability and identify optimal treatment strategies for individual patients. To address this, we analyzed responses to nusinersen and risdiplam in 45 primary fibroblast cell lines. Pre-treatment SMN2-FL, SMN2Δ7 mRNA, and SMN protein levels were influenced by SMN2 copy number, age, and sex. After treatment, SMN and mRNA levels were more heterogeneous. In 43% of patients, response to both therapies was similar, but in 57% one treatment led to a significantly higher SMN increase than the other treatment. Younger age, higher SMN2 copy number, and higher SMN levels before treatment predicted better in vitro efficacy. These findings showcase patient-derived fibroblasts as a tool for identifying molecular predictors for personalized treatment.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"32 4","pages":"101379"},"PeriodicalIF":4.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11626024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0