Human gene therapy最新文献

{"title":"Akouos Therapy Restores 11-Year-Old Boy's Hearing After 1 Month.","authors":"Alex Philippidis","doi":"10.1089/hum.2024.29267.bfs","DOIUrl":"10.1089/hum.2024.29267.bfs","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 5-6","pages":"135-138"},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143321","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":"Current Status and Prospects of Viral Vector-Based Gene Therapy to Treat Kidney Diseases.","authors":"Louise Medaer, Koenraad Veys, Rik Gijsbers","doi":"10.1089/hum.2023.184","DOIUrl":"10.1089/hum.2023.184","url":null,"abstract":"<p><p>Inherited kidney diseases are among the leading causes of chronic kidney disease, reducing the quality of life and resulting in substantial socioeconomic impact. The advent of early genetic testing and the growing understanding of the molecular basis and pathophysiology of these disorders have opened avenues for novel treatment strategies. Viral vector-based gene therapies have evolved from experimental treatments for rare diseases to potent platforms that carry the intrinsic potential to provide a cure with a single application. Several gene therapy products have reached the market, and the numbers are only expected to increase. Still, none target inherited kidney diseases. Gene transfer to the kidney has lagged when compared to other tissue-directed therapies such as hepatic, neuromuscular, and ocular tissues. Systemic delivery of genetic information to tackle kidney disease is challenging. The pharma industry is taking steps to take on kidney disease and to translate the current research into the therapeutic arena. In this review, we provide an overview of the current viral vector-based approaches and their potential. We discuss advances in platforms and injection routes that have been explored to enhance gene delivery toward kidney cells in animal models, and how these can fuel the development of viable gene therapy products for humans.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"139-150"},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930889","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":"Gutless Helper-Dependent and First-Generation HAdV5 Vectors Have Similar Mechanical Properties and Common Transduction Mechanisms.","authors":"Lars Thalmann, Natalia Martin-Gonzalez, Dominik Brücher, Andreas Plückthun, Pedro J de Pablo, Maarit Suomalainen, Urs F Greber","doi":"10.1089/hum.2023.221","DOIUrl":"10.1089/hum.2023.221","url":null,"abstract":"<p><p>Delivering vectorized information into cells with the help of viruses has been of high interest to fundamental and applied science, and bears significant therapeutic promise. Human adenoviruses (HAdVs) have been at the forefront of gene delivery for many years, and the subject of intensive development resulting in several generations of agents, including replication-competent, -defective or retargeted vectors, and recently also helper-dependent (HD), so-called gutless vectors lacking any viral protein coding information. While it is possible to produce HD-AdVs in significant amounts, physical properties of these virus-like particles and their efficiency of transduction have not been addressed. Here, we used single-cell and single virus particle assays to probe the effect of genome length on HAdV-C5 vector transduction. Our results demonstrate that first-generation C5 vectors lacking the E1/E3 regions of the viral genome as well as HD-AdV-C5 particles with a wild type (wt) ∼36 kbp or an undersized double-strand DNA genome are similar to human adenovirus C5 (HAdV-C5) wt regarding attachment to human lung epithelial cells, endocytic uptake, endosome penetration and dependency on the E3 RING ubiquitin ligase Mind Bomb 1 for DNA uncoating at the nuclear pore complex. Atomic force microscopy measurements of single virus particles indicated that small changes in the genome length from 94% to 103% of HAdV-C5 have no major impact on physical and mechanical features of AdV vectors. In contrast, an HD-AdV-C5 with ∼30 kbp genome was slightly stiffer and less heat-resistant than the other particles, despite comparable entry and transduction efficiencies in tissue culture cell lines, including murine alveolar macrophage-like Max-Planck-Institute (MPI)-2 cells. Together, our <i>in vitro</i> studies reinforce the use of HD-AdV vectors for effective single round gene delivery. The results illustrate how physical properties and cell entry behavior of single virus particles can provide functional information for anticipated therapeutic vector applications.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"163-176"},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930890","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":"Kenneth I. Berns, MD, PhD [1938-2024].","authors":"Barry J Byrne, Terence R Flotte, Roland W Herzog, Arun Srivastava","doi":"10.1089/hum.2024.29266.kib","DOIUrl":"10.1089/hum.2024.29266.kib","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 5-6","pages":"133-134"},"PeriodicalIF":4.2,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143322","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 Paradox of the Field's Own Success: Unintended Challenges in Bringing Cutting-Edge Science from the Bench to the Market.","authors":"Nathan Yingling, Miguel Sena-Esteves, Heather L Gray-Edwards","doi":"10.1089/hum.2023.29264.nyi","DOIUrl":"10.1089/hum.2023.29264.nyi","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 3-4","pages":"83-88"},"PeriodicalIF":4.2,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912532","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":"Danaher Partners with Innovative Genomics Institute, Doudna, and Urnov on Beacon for CRISPR Cures.","authors":"Alex Philippidis","doi":"10.1089/hum.2024.29265.bfs","DOIUrl":"10.1089/hum.2024.29265.bfs","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":"35 3-4","pages":"89-92"},"PeriodicalIF":4.2,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912533","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":"Adeno-Associated Virus Type 9-Mediated Gene Therapy of Choline Acetyltransferase-Deficient Mice.","authors":"Cameron V Lin, Clementine A D Thomas, Thanh L Huynh, David T Wei, Jaime N Young, Anahid S Aivazian, Abigail McInnes, Jixiang Xu, Sarah E Cook, Jessica Vazquez, Ricardo A Maselli","doi":"10.1089/hum.2023.173","DOIUrl":"10.1089/hum.2023.173","url":null,"abstract":"<p><p>The enzyme choline acetyltransferase (ChAT) synthesizes acetylcholine from acetyl-CoA and choline at the neuromuscular junction and at the nerve terminals of cholinergic neurons. Mutations in the ChAT gene (<i>CHAT</i>) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for <i>Chat (Chat^-/-)</i> die at birth. To circumvent the lethality of this model, we crossed mutant mice possessing <i>loxP</i> sites flanking <i>Chat</i> exons 4 and 5 with mice that expressed <i>Cre-ER^T2</i>. Injection of tamoxifen (Tx) at postnatal (P) day 11 in these mice induced downregulation of <i>Chat</i>, autonomic failure, weakness, and death. However, a proportion of <i>Chat^flox/flox-Cre-ER^T2</i> mice receiving at birth an intracerebroventricular injection of 2 × 10¹³ vg/kg adeno-associated virus type 9 (AAV9) carrying human <i>CHAT</i> (AAV9-<i>CHAT</i>) survived a subsequent Tx injection and lived to adulthood without showing signs of weakness. Likewise, injection of AA9-<i>CHAT</i> by intracisternal injection at P28 after the onset of weakness also resulted in survival to adulthood. The expression of Chat in spinal motor neurons of <i>Chat^flox/flox-Cre-ER^T2</i> mice injected with Tx was markedly reduced, but AAV-injected mice showed a robust recovery of ChAT expression, which was mainly translated by the human <i>CHAT</i> RNA. The biodistribution of the viral genome was widespread but maximal in the spinal cord and brain of AAV-injected mice. No significant histopathological changes were observed in the brain, liver, and heart of AAV-injected mice after 1 year follow-up. Thus, AAV9-mediated gene therapy may provide an effective and safe treatment for patients severely affected with <i>CHAT-</i>CMS.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"123-131"},"PeriodicalIF":3.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650613","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":"Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis.","authors":"Zeyu Han, Xianyanling Yi, Jin Li, Dazhou Liao, Guangping Gao, Jianzhong Ai","doi":"10.1089/hum.2023.208","DOIUrl":"10.1089/hum.2023.208","url":null,"abstract":"<p><p>Clinical trials of adeno-associated virus (AAV)-based gene therapy have made remarkable progress in recent years. We aimed to perform a systematic review and meta-analysis of the literature to assess the efficacy and safety of AAV-based gene therapy for hemophilia. We systematically searched the Web of Science, Embase, PubMed, and the Cochrane Database of Systematic Reviews databases, for clinical trials involving patients diagnosed with hemophilia and treated with AAV-mediated gene therapy. Data on the annualized bleeding rate (ABR), annualized infusion rate (AIR), the incidence of treatment-related adverse events (TRAEs), severe adverse events (SAEs), and alanine aminotransferase (ALT) elevation were extracted as our outcomes. A total of 12 articles from 11 clinical trials were selected from 868 articles for meta-analysis. Pooled analyses showed that AAV-based gene therapy in hemophilia patients reduced the number of bleeding events and the number of factor infusion events by an approximate average of 7 per year and 103 per year, respectively. Eighty percent, 18%, and 63% of hemophilia patients had elevated TRAE, SAE, and ALT levels, respectively. Moreover, subgroup analysis found a significant reduction in ABR and AIR 2-3 years after the therapy. Additional findings that were not pooled including coagulation factor activity are presented in the accompanying tables. Our analysis supported the efficacy and safety of AAV-mediated gene therapy for hemophilia, providing evidence for its application as a therapeutic option for widespread clinical use in hemophilia patients in the future.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"93-103"},"PeriodicalIF":3.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377484","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":"Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.","authors":"Rui Li, Ling Zhang, Chen Peng, Yanmei Lu, Zhihao Liu, Xiao Xu, Changyi Wang, Ruijie Hu, Wuping Tan, Liping Zhou, Yueyi Wang, Lilei Yu, Yuhong Wang, Baopeng Tang, Hong Jiang","doi":"10.1089/hum.2023.160","DOIUrl":"10.1089/hum.2023.160","url":null,"abstract":"<p><p>The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH⁺) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. <i>In vivo</i>, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"114-122"},"PeriodicalIF":3.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138827098","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":"Drug Repositioning for Amyloid Transthyretin Amyloidosis by Interactome Network Corrected by Graph Neural Networks and Transcriptome Analysis.","authors":"Shan He, XiaoYing Lv, XinYue He, JinJiang Guo, RuoKai Pan, YuTong Jin, Zhuang Tian, LuRong Pan, ShuYang Zhang","doi":"10.1089/hum.2021.222","DOIUrl":"10.1089/hum.2021.222","url":null,"abstract":"<p><p>Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"70-79"},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41122240","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}