Human gene therapy最新文献

{"title":"Prevalence of Adeno-Associated Virus-9-Neutralizing Antibody in Chinese Patients with Duchenne Muscular Dystrophy.","authors":"Cuijie Wei, Dongliang Li, Meng Zhang, Yanping Zhao, Yidan Liu, Yanbin Fan, Lu Wang, Jieyu Liu, Xingzhi Chang, Yuwu Jiang, Hui Xiong","doi":"10.1089/hum.2023.117","DOIUrl":"10.1089/hum.2023.117","url":null,"abstract":"<p><p>The delivery of a mini-dystrophin gene to skeletal muscles using recombinant adeno-associated virus serotype (AAV) holds great potential as a gene therapy for Duchenne muscular dystrophy (DMD). However, the presence of anti-AAV-neutralizing antibodies (NAbs) may impede the effectiveness of gene transduction. This study aimed to evaluate the prevalence of anti-AAV9 NAbs in Chinese patients with DMD, and to characterize the target population for an AAV gene therapy. A total of one hundred male patients with DMD were included in this study, and demographic and clinical data were collected. A blood specimen was obtained from each participant for the purpose of evaluating the existence of anti-AAV9 NAbs through a cell-based functional assay conducted at a central laboratory. A NAb titer exceeding 1:4 was considered positive. The positivity rates of anti-AAV9 NAb were compared among different subgroups. The median age of this DMD cohort was 8 years old, ranging from 3 to 15 years of age. Forty-two percent of patients tested positive for anti-AAV9 NAb. Notably, all samples from patients under 4 years of age tested negative, and the positivity rates of anti-AAV9 NAb differed significantly across the three age subgroups (<4 years old, ≥4 years old and <12 years old, and ≥12 years old, <i>χ</i>² = 7.221, <i>p</i> = 0.023). Further investigation into the living environment revealed a higher positivity rate of anti-AAV9 NAb in rural patients compared with urban patients (<i>χ</i>² = 3.923, <i>p</i> = 0.048). Moreover, the prevalence in patients from different cities/provinces varied greatly (<i>χ</i>² = 16.550, <i>p</i> = 0.003). There was no statistically significant difference in the positivity rate of NAb among subgroups of patients with different motor functions (ambulatory or nonambulatory) and different treatment strategies (taking or not taking glucocorticoid). In Chinese DMD patients, the prevalence of anti-AAV9 NAb was found to reach 42%. Moreover, the antibody-positive rate in children <4 years of age was low and revealed notable regional discrepancies.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"26-35"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138798924","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}

{"title":"Creating an Innovation Engine to Advance Medicine for Patients with Rare Diseases.","authors":"Thomas Gallagher","doi":"10.1089/hum.2024.98456","DOIUrl":"10.1089/hum.2024.98456","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1-6"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921521","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}

{"title":"A Recombinant Oncolytic Influenza Virus Carrying GV1001 Triggers an Antitumor Immune Response.","authors":"Cong Li, Yuying Tian, Fang Sun, Guanglin Lei, Jinxia Cheng, Chongyu Tian, Hongyu Yu, Zhuoya Deng, Shuai Lu, Lishi Wang, Ruixue Xiao, Changqing Bai, Penghui Yang","doi":"10.1089/hum.2022.206","DOIUrl":"10.1089/hum.2022.206","url":null,"abstract":"<p><p>Oncolytic viruses are able to lyse tumor cells selectively in the liver without killing normal hepatocytes, in addition to activating the immune response. Oncolytic virus therapy is expected to revolutionize the treatment of liver cancer, including hepatocellular carcinoma (HCC), one of the most frequent and fatal malignancies. In this study, reverse genetics techniques were exploited to load NA fragments of the A/PuertoRico/8/34 virus (PR8) with GV1001 peptides derived from human telomerase reverse transcriptase. An <i>in vitro</i> assessment of the therapeutic effect of the recombinant oncolytic virus was followed by an <i>in vivo</i> study in mice with HCC. The recombinant virus was verified by sequencing of the recombinant viral gene sequence, and viral virulence was detected by hemagglutination assays and based on the 50% tissue culture infectious dose (TCID₅₀). The morphological structure of the virus was observed by electron microscopy, and GV1001 peptide was localized by cellular immunofluorescence. The selective cytotoxicity of the recombinant oncolytic virus <i>in vitro</i> was demonstrated in cultured HCC cells and normal hepatocytes, as only the tumor cells were killed; the normal cells were not significantly altered. Consistent with the <i>in vitro</i> results, the recombinant oncolytic influenza virus significantly inhibited liver tumor growth in mice <i>in vivo</i>, in addition to inducing an antitumor immune response, including an increase in the number of CD4⁺ and CD8⁺ T lymphocytes and, in turn, improving survival. Our results suggest that oncolytic influenza virus carrying GV1001 is a promising immunotherapy in patients with HCC.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"48-58"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168178","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}

{"title":"Acknowledgment of Reviewers 2024.","authors":"","doi":"10.1089/hum.2024.11232.revack","DOIUrl":"https://doi.org/10.1089/hum.2024.11232.revack","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"36 1-2","pages":"57-58"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004581","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}

{"title":"Twenty-Year Survival Analysis of Adeno-Associated Virus Vector Serotype 2-Mediated Gene Therapy to the Central Nervous System for CLN2 Disease.","authors":"Dolan Sondhi, Stephen M Kaminsky, Jonathan B Rosenberg, Mahboubeh R Rostami, Neil R Hackett, Ronald G Crystal","doi":"10.1089/hum.2024.182","DOIUrl":"10.1089/hum.2024.182","url":null,"abstract":"<p><p>CLN2 disease (late infantile neuronal ceroid lipofuscinosis) is an autosomal recessive, neurodegenerative lysosomal storage disease that results from loss of function mutations in the <i>CLN2</i> gene, which encodes tripeptidyl peptidase 1. It affects the central nervous system (CNS) with progressive neurodegeneration and early death, typically at ages from 8 to 12 years. Twenty years ago, our phase I clinical trial treated subjects with CLN2 disease by a catheter-based CNS administration of an adeno-associated virus vector serotype 2 (AAV2) expressing the <i>CLN2</i> gene. Here we present an analysis of the survival of the 10 treated children and find 2 distinct survival groups with a wide disparity in survival. Group 1 (<i>n</i> = 7) had the typical mean survival of 8.8 ± 0.5 years of age, 3.8 ± 0.6 years post-therapy. Group 2 (<i>n</i> = 3) had a markedly longer mean survival of 23.4 ± 2.4 years of age and 14.9 ± 2.8 years post-therapy (<i>p</i> < 0.00002, survival of group 1 vs. group 2). Long survivors (group 2) at the time of treatment were older (group 1: 5.0 ± 0.6 years; group 2: 8.5 ± 0.9 years; <i>p</i> < 0.02); had similar disease severity (Hamburg clinical score group 1: 4.7 ± 0.5, group 2: 3 ± 0.0, <i>p</i> > 0.05); and had larger CNS ventricular volume (81.1 ± 22.2 cm³ vs. 27.3 ± 7.2 cm³ for group 1; <i>p</i> < 0.02). While the genotype of 3, group 2 subjects, had one allele (509-1G>C) identical to that of three in group 1, the second allele was different. This was unlikely to explain the survival difference, as alleles for both groups were equally predicted deleterious by the Combined Annotation-Dependent Depletion score: 34.9 ± 0.7 and 32.8 ± 0.3 for groups 1 and 2, respectively (a score of >20 is considered deleterious). This represents one of the longest survival studies (up to 20 years) of AAV-treated individuals with hereditary disorders and demonstrates variability of therapeutic efficacy where the genotype on its own has no apparent survival advantage. Protocol registration numbers for the original study: NCT00151216 and NCT00151268; www.clinicaltrials.gov.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"28-35"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914654","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}

{"title":"Boy Dosed with Pfizer's Duchenne Muscular Dystrophy Gene Therapy Dies a Year After Phase II Trial.","authors":"Alex Philippidis","doi":"10.1089/hum.2024.53426.bfs","DOIUrl":"10.1089/hum.2024.53426.bfs","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"7-10"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563275","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}

{"title":"Leveraging CRISPR-Cas9 for Accurate Detection of AAV Neutralizing Antibodies: The AAV-HDR Method","authors":"Guohua Li, Saining Tian, Xin-Yu Sun, Mei Zhao, Feng Zhang, Jianping Zhang, Tao Cheng, Xiao-Bing Zhang","doi":"10.1089/hum.2023.129","DOIUrl":"https://doi.org/10.1089/hum.2023.129","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"4 24","pages":""},"PeriodicalIF":4.2,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138586097","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}

{"title":"Concise analysis of single-stranded DNA of recombinant adeno-associated virus by automated electrophoresis system","authors":"Yuzhe Yuan, Kiyoko Higashiyama, Noriko Hashiba, K. Masumi‐Koizumi, Keisuke Yusa, Kazuhisa Uchida","doi":"10.1089/hum.2023.148","DOIUrl":"https://doi.org/10.1089/hum.2023.148","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"52 21","pages":""},"PeriodicalIF":4.2,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593246","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}

{"title":"The British Society for Gene and Cell Therapy at 20 (2003-2023)","authors":"Leonard W. Seymour, A. Thrasher, Andrew H Baker, U. Griesenbach, Rafael J. Yáñez-Muñoz","doi":"10.1089/hum.2023.196","DOIUrl":"https://doi.org/10.1089/hum.2023.196","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 21","pages":""},"PeriodicalIF":4.2,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138592115","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}

{"title":"Multidimensional Response Surface Methodology for the development of a gene editing protocol for p67phox-deficient Chronic Granulomatous Disease.","authors":"Thomas E. Whittaker, Shefta-E Moula, Sameer Bahal, Faris G Bakri, W. Hayajneh, Ammar K Daoud, Asma Naseem, Alessia Cavazza, A. Thrasher, G. Santilli","doi":"10.1089/hum.2023.114","DOIUrl":"https://doi.org/10.1089/hum.2023.114","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"59 13","pages":""},"PeriodicalIF":4.2,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138593427","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}