Gene TherapyPub Date : 2024-03-12DOI: 10.1038/s41434-024-00447-z
Felix Krause, Katja Schmidtke, Mailton Franca de Vasconcelos, David Schmidt, Beyza Cansiz, Franziska Theisen, Melanie D. Mark, Max O. Rybarski
{"title":"A shedding analysis after AAV8 CNS injection revealed fragmented viral DNA without evidence of functional AAV particles in mice","authors":"Felix Krause, Katja Schmidtke, Mailton Franca de Vasconcelos, David Schmidt, Beyza Cansiz, Franziska Theisen, Melanie D. Mark, Max O. Rybarski","doi":"10.1038/s41434-024-00447-z","DOIUrl":"10.1038/s41434-024-00447-z","url":null,"abstract":"Adeno-associated viruses (AAV) are commonly used in the scientific field due to their diverse application range. However, AAV shedding, the release of virions from the host organism, can impact the safety of AAV-based approaches. An increasing number of authorities require the characterization of vector shedding in clinical trials. Recently, shedding of transduced laboratory animals has also gained attention regarding the necessary disposal measures of their waste products. However, no explicit international regulations for AAV-shedding waste exist. Generating insights into shedding dynamics becomes increasingly relevant to help authorities develop adequate regulations. To date, knowledge of AAV vector shedding in mice is very limited. Moreover, confirmation of functional shed AAV particles in mice is missing. Therefore, we examined feces, urine, and saliva of mice after CNS injection with AAV2/8. It revealed the presence of viral DNA fragments via qPCR for up to 4 days after injection. To examine AAV functionality we performed nested PCR and could not detect full-length viral genomes in any but two collected feces samples. Furthermore, a functional infection assay did not reveal evidence of intact AAV particles. Our findings are supposed to contribute murine shedding data as a foundation to help establish still lacking adequate biosafety regulations in the context of AAV shedding.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00447-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Are genetically modified protozoa eligible for ATMP status? Concerning the legal categorization of an oncolytic protozoan drug candidate","authors":"Mathieu Guerriaud, Cyril Poupet, Zineb Lakhrif, Evelyne Kohli, Nathalie Moiré","doi":"10.1038/s41434-024-00445-1","DOIUrl":"10.1038/s41434-024-00445-1","url":null,"abstract":"Neospora caninum is an obligate intracellular protozoan that affects several animal species. It is not pathogenic for humans, and its ability to infect and lyse a variety of cells and stimulate the immune system makes it an interesting drug candidate in oncology. The intrinsic oncolytic properties of N. caninum have been confirmed in several preclinical models. Moreover, it can be modified to improve its safety and/or efficacy against cancer cells. In this study, we propose the legal categorization of this new biological drug candidate and the impact of modifications, notably the integration of a suicide gene, the deletion of a gene allowing its multiplication in healthy cells, and/or the insertion of a gene coding for a therapeutic protein into its genome. When unmodified, N. caninum can be categorized as a biological medicinal product, whereas modifications aimed at increasing its safety classify it as a Somatic Cell Therapy Medicinal Product, and modifications aiming to increase its efficacy or both safety and efficacy make it as a Gene Therapy Medicinal Product. This categorization is fundamental because it determines the guidelines applicable for preclinical development. These guidelines being numerous and complex, we have focused on the key requirements necessary for the development of the future medicinal product.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140001530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-02-19DOI: 10.1038/s41434-024-00444-2
Aisleen McColl-Carboni, Serena Dollive, Sarah Laughlin, Rudenc Lushi, Michael MacArthur, Shanshan Zhou, Jeffrey Gagnon, Christopher A. Smith, Brenda Burnham, Robert Horton, Dimpal Lata, Brianna Uga, Kalyani Natu, Emmanuela Michel, Celia Slater, Evan DaSilva, Robert Bruccoleri, Tim Kelly, James B. McGivney IV
{"title":"Analytical characterization of full, intermediate, and empty AAV capsids","authors":"Aisleen McColl-Carboni, Serena Dollive, Sarah Laughlin, Rudenc Lushi, Michael MacArthur, Shanshan Zhou, Jeffrey Gagnon, Christopher A. Smith, Brenda Burnham, Robert Horton, Dimpal Lata, Brianna Uga, Kalyani Natu, Emmanuela Michel, Celia Slater, Evan DaSilva, Robert Bruccoleri, Tim Kelly, James B. McGivney IV","doi":"10.1038/s41434-024-00444-2","DOIUrl":"10.1038/s41434-024-00444-2","url":null,"abstract":"Manufacturing of recombinant adeno-associated virus (AAV) vectors produces three types of capsids: full, intermediate, and empty. While there are different opinions about the impact of intermediate and empty capsids on safety and efficacy of AAV products, they are generally considered impurities because they are not the intended fully intact vector product. The presence of these impurities could impact product efficacy due to potential competition with fully packaged AAVs for cellular transduction, as well as have potential implications to patient safety due to increased capsid load during dosing. To determine the impact of intermediate capsids on potency, an AAV preparation was separated into fractions enriched for full, intermediate, or empty capsids. Using a matrix of in vitro (infectivity, gene expression, biological activity) and in vivo potency assays to determine potency as a function of capsid content, our results indicate that while intermediate capsids contribute to the vector genome titer of the product and are equally as infectious as full capsids, they do not contribute to the potency of the AAV product. This study confirms the criticality of reducing and controlling the level of intermediate capsids to ensure a more efficacious AAV product.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00444-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-02-14DOI: 10.1038/s41434-024-00441-5
Ingrid Pabinger, Mila Ayash-Rashkovsky, Miguel Escobar, Barbara A. Konkle, María Eva Mingot-Castellano, Eric S. Mullins, Claude Negrier, Luying Pan, Kavitha Rajavel, Brian Yan, John Chapin
{"title":"Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia","authors":"Ingrid Pabinger, Mila Ayash-Rashkovsky, Miguel Escobar, Barbara A. Konkle, María Eva Mingot-Castellano, Eric S. Mullins, Claude Negrier, Luying Pan, Kavitha Rajavel, Brian Yan, John Chapin","doi":"10.1038/s41434-024-00441-5","DOIUrl":"10.1038/s41434-024-00441-5","url":null,"abstract":"Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00441-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Gene therapy corrects the neurological deficits of mice with sialidosis","authors":"Wuh-Liang Hwu, Karine Chang, Yu-Han Liu, Hao-Chun Wang, Ni-Chung Lee, Yin-Hsiu Chien","doi":"10.1038/s41434-024-00443-3","DOIUrl":"10.1038/s41434-024-00443-3","url":null,"abstract":"Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1−/−) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1−/− mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1−/− mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1−/− mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-01-26DOI: 10.1038/s41434-024-00440-6
Shannon M. McNamee, Natalie P. Chan, Monica Akula, Marielle O. Avola, Maiya Whalen, Kaden Nystuen, Pushpendra Singh, Arun K. Upadhyay, Margaret M. DeAngelis, Neena B. Haider
{"title":"Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/−","authors":"Shannon M. McNamee, Natalie P. Chan, Monica Akula, Marielle O. Avola, Maiya Whalen, Kaden Nystuen, Pushpendra Singh, Arun K. Upadhyay, Margaret M. DeAngelis, Neena B. Haider","doi":"10.1038/s41434-024-00440-6","DOIUrl":"10.1038/s41434-024-00440-6","url":null,"abstract":"Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H−/− mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/− mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00440-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139564014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-01-26DOI: 10.1038/s41434-024-00442-4
María del Pilar Plastine, Sabrina Amalfi, María Gabriela López, María José Gravisaco, Oscar Taboga, Victoria Alfonso
{"title":"Development of a stable Sf9 insect cell line to produce VSV-G pseudotyped baculoviruses","authors":"María del Pilar Plastine, Sabrina Amalfi, María Gabriela López, María José Gravisaco, Oscar Taboga, Victoria Alfonso","doi":"10.1038/s41434-024-00442-4","DOIUrl":"10.1038/s41434-024-00442-4","url":null,"abstract":"Baculoviruses have shown great potential as gene delivery vectors in mammals, although their effectiveness in transferring genes varies across different cell lines. A widely employed strategy to improve transduction efficiency is the pseudotyping of viral vectors. In this study, we aimed to develop a stable Sf9 insect cell line that inducibly expresses the G-protein of the vesicular stomatitis virus to pseudotype budded baculoviruses. It was obtained by inserting the VSV-G gene under the control of the very strong and infection-inducible pXXL promoter and was subsequently diluted to establish oligoclonal lines, which were selected by the fusogenic properties of VSV-G and its expression levels in infected cells and purified budded virions. Next, to enhance the performance of the cell line, the infection conditions under which functional pseudotyped baculoviruses are obtained were optimized. Finally, different baculoviruses were pseudotyped and the expression of the transgene was quantified in mammalian cells of diverse origins using flow cytometry. The transduction efficiency of pseudotyped baculovirus consistently increased across all tested mammalian cell lines compared with control viruses. These findings demonstrate the feasibility and advantages of improving gene delivery performance without the need to insert the pseudotyping gene into the baculoviral genomes.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-01-12DOI: 10.1038/s41434-023-00438-6
Tricia H. Burdo, Chen Chen, Rafal Kaminski, Ilker K. Sariyer, Pietro Mancuso, Martina Donadoni, Mandy D. Smith, Rahsan Sariyer, Maurizio Caocci, Shuren Liao, Hong Liu, Wenwen Huo, Huaqing Zhao, John Misamore, Mark G. Lewis, Vahan Simonyan, Elaine E. Thompson, Ethan Y. Xu, Thomas J. Cradick, Jennifer Gordon, Kamel Khalili
{"title":"Correction: Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates","authors":"Tricia H. Burdo, Chen Chen, Rafal Kaminski, Ilker K. Sariyer, Pietro Mancuso, Martina Donadoni, Mandy D. Smith, Rahsan Sariyer, Maurizio Caocci, Shuren Liao, Hong Liu, Wenwen Huo, Huaqing Zhao, John Misamore, Mark G. Lewis, Vahan Simonyan, Elaine E. Thompson, Ethan Y. Xu, Thomas J. Cradick, Jennifer Gordon, Kamel Khalili","doi":"10.1038/s41434-023-00438-6","DOIUrl":"10.1038/s41434-023-00438-6","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00438-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-01-10DOI: 10.1038/s41434-023-00436-8
Brahim Chaqour, Thu T. Duong, Jipeng Yue, Tehui Liu, David Camacho, Kimberly E. Dine, Julian Esteve-Rudd, Scott Ellis, Jean Bennett, Kenneth S. Shindler, Ahmara G. Ross
{"title":"AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes","authors":"Brahim Chaqour, Thu T. Duong, Jipeng Yue, Tehui Liu, David Camacho, Kimberly E. Dine, Julian Esteve-Rudd, Scott Ellis, Jean Bennett, Kenneth S. Shindler, Ahmara G. Ross","doi":"10.1038/s41434-023-00436-8","DOIUrl":"10.1038/s41434-023-00436-8","url":null,"abstract":"Recombinant adeno-associated virus (AAV)-2 has significant potential as a delivery vehicle of therapeutic genes to retinal ganglion cells (RGCs), which are key interventional targets in optic neuropathies. Here we show that when injected intravitreally, AAV2 engineered with a reporter gene driven by cytomegalovirus (CMV) enhancer and chicken β-actin (CBA) promoters, displays ubiquitous and high RGC expression, similar to its synthetic derivative AAV8BP2. A novel AAV2 vector combining the promoter of the human RGC-selective γ-synuclein (hSNCG) gene and woodchuck hepatitis post-transcriptional regulatory element (WPRE) inserted upstream and downstream of a reporter gene, respectively, induces widespread transduction and strong transgene expression in RGCs. High transduction efficiency and selectivity to RGCs is further achieved by incorporating in the vector backbone a leading CMV enhancer and an SV40 intron at the 5’ and 3’ ends, respectively, of the reporter gene. As a delivery vehicle of hSIRT1, a 2.2-kb therapeutic gene with anti-apoptotic, anti-inflammatory and anti-oxidative stress properties, this recombinant vector displayed improved transduction efficiency, a strong, widespread and selective RGC expression of hSIRT1, and increased RGC survival following optic nerve crush. Thus, AAV2 vector carrying hSNCG promoter with additional regulatory sequences may offer strong potential for enhanced effects of candidate gene therapies targeting RGCs.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gene TherapyPub Date : 2024-01-10DOI: 10.1038/s41434-023-00437-7
Hyeokgyo Jeong, Sujata Purja, Eunyoung Kim
{"title":"Analysis and comparative evaluation of expedited programs for gene therapy products: insights from the United States, the European Union, Japan, and South Korea","authors":"Hyeokgyo Jeong, Sujata Purja, Eunyoung Kim","doi":"10.1038/s41434-023-00437-7","DOIUrl":"10.1038/s41434-023-00437-7","url":null,"abstract":"Gene therapy products (GTPs) used for incurable diseases can be expedited for early commercialization to fulfill unmet needs. This study analyzed the expedited programs available for GTPs in the US, EU, Japan, and South Korea using their regulatory authorities’ websites, related regulations, and documents. In total, there were five expedited programs available for GTPs in the US, four in the EU, and three in both Japan and South Korea, of which four are tailored for GTPs. These programs, sharing similar objectives, can be categorized as those expediting drug development, review, and approval. However, variations are observed in eligibility criteria, specific benefits, and post-marketing study conditions across regulatory authorities. Additionally, the criteria for orphan drug designation for a rare disease differs in prevalence thresholds, incentive offered, and marketing exclusivity period. Overall, 19 GTPs were approved–13 in the US, 14 in the EU, eight in Japan, and three in South Korea–with majority obtaining regulatory approval through at least one expedited program. Therefore, future studies can analyze whether acquiring multiple expedited programs accelerates the drug development and commercialization of GTPs compared with when only one expedited program is processed. Additionally, inter-authority scientific discussion is encouraged for harmonization of expedited program requirements.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139415328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}