Human gene therapy最新文献_第10页

Introduction to ESGCT 2024 Special Issue. ESGCT 2024 特刊简介。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 DOI: 10.1089/hum.2024.35178

Alberto Auricchio

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Modulation of AAV9 Galactose Binding Yields Novel Gene Therapy Vectors and Predicts Cross-Species Differences in Glycan Avidity. 调节 AAV9 的半乳糖结合可产生新的基因治疗载体，并可预测糖酶活性的跨物种差异。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-08-13 DOI: 10.1089/hum.2024.050

Jacob A Hoffman, Nathan Denton, Joshua J Sims, Rosemary Meggersee, Zhe Zhang, Kanyin Olagbegi, James M Wilson

{"title":"Modulation of AAV9 Galactose Binding Yields Novel Gene Therapy Vectors and Predicts Cross-Species Differences in Glycan Avidity.","authors":"Jacob A Hoffman, Nathan Denton, Joshua J Sims, Rosemary Meggersee, Zhe Zhang, Kanyin Olagbegi, James M Wilson","doi":"10.1089/hum.2024.050","DOIUrl":"10.1089/hum.2024.050","url":null,"abstract":"Effective use of adeno-associated viruses (AAVs) for clinical gene therapy is limited by their propensity to accumulate in and transduce the liver. This natural liver tropism is associated with severe adverse events at the high doses that can be necessary for achieving therapeutic transgene expression in extrahepatic tissues. To improve the safety and cost of AAV gene therapy, capsid engineering efforts are underway to redirect in vivo AAV biodistribution away from the liver toward disease-relevant peripheral organs such as the heart. Building on previous work, we generated a series of AAV libraries containing variations at three residues (Y446, N470, and W503) of the galactose-binding pocket of the AAV9 VP1 protein. Screening of this library in mice identified the XRH family of variants (Y446X, N470R, and W503H), the strongest of which, HRH, exhibited a 6-fold reduction in liver RNA expression and a 10-fold increase in cardiac RNA expression compared with wild-type AAV9 in the mouse. Screening of our library in a nonhuman primate (NHP) revealed reduced performance of AAV9 and two closely related vectors in the NHP liver compared with the mouse liver. Measurement of the galactose-binding capacity of our library further identified those same three vectors as the only strong galactose binders, suggesting an altered galactose presentation between the mouse and NHP liver. N-glycan profiling of these tissues revealed a 9% decrease in exposed galactose in the NHP liver compared with the mouse liver. In this work, we identified a novel family of AAV variants with desirable biodistribution properties that may be suitable for targeting extrahepatic tissues such as the heart. These data also provide important insights regarding species- and tissue-specific differences in glycan presentation that may have implications for the development and translation of AAV gene therapies.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"734-753"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603567","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}

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Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for Human Gene Therapy. 罗莎琳德-富兰克林学会自豪地宣布 2023 年人类基因疗法奖获得者。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 DOI: 10.1089/hgt.2024.32445.rfs2023

Gloria Gonzalez Aseguinolaza

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Lipid Nanoparticles for Nucleic Acid Delivery Beyond the Liver. 用于在肝脏外输送核酸的脂质纳米颗粒。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-08-28 DOI: 10.1089/hum.2024.106

Nadine Saber, Mariona Estapé Senti, Raymond M Schiffelers

引用次数: 0

Advances in MicroRNA Therapeutics: From Preclinical to Clinical Studies. 微RNA疗法的进展：从临床前研究到临床研究。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 DOI: 10.1089/hum.2024.113

Simona Brillante, Mariagrazia Volpe, Alessia Indrieri

{"title":"Advances in MicroRNA Therapeutics: From Preclinical to Clinical Studies.","authors":"Simona Brillante, Mariagrazia Volpe, Alessia Indrieri","doi":"10.1089/hum.2024.113","DOIUrl":"10.1089/hum.2024.113","url":null,"abstract":"MicroRNAs (miRNAs) are crucial regulators of gene expression involved in various pathophysiological processes. Their ability to modulate multiple pathways simultaneously and their involvement in numerous diseases make miRNAs attractive tools and targets in therapeutic development. Significant efforts have been made to advance miRNA research in the preclinical stage, attracting considerable investment from biopharmaceutical companies. Consequently, an increasing number of miRNA-based therapies have entered clinical trials for both diagnostic and therapeutic applications across a wide range of diseases. While individual miRNAs can regulate a broad array of mRNA targets, this also complicates the management of adverse effects seen in clinical trials. Several candidates have been discontinued due to toxicity concerns, underscoring the need for comprehensive risk assessments of miRNA therapeutics. Despite no miRNA-based strategies have yet received approval from regulatory agencies, prominent progress in the miRNA modulation approaches and in the nano-delivery systems have been made in the last decade, leading to the development of novel safe and well-tolerated miRNA drug candidates. In this review, we present recent advances in the development of miRNA therapeutics currently in preclinical or clinical stages for treating both rare genetic disorders and multifactorial common conditions. We also address the challenges related to the safety and targeted delivery of miRNA therapies, as well as the identification of the most effective therapeutic candidates in preclinical and clinical trials.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"628-648"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987878","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}

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Call for Papers: Special Issue on Toxicity And Safety in Clinical AAV Gene Therapy. 征稿启事：临床 AAV 基因疗法的毒性和安全性特刊。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 DOI: 10.1089/hum.2024.85296

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Insights into Prime Editing Technology: A Deep Dive into Fundamentals, Potentials, and Challenges. 深入了解基因编辑技术：深入探讨基本原理、潜力和挑战。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-07-01 DOI: 10.1089/hum.2024.043

Seyed Younes Hosseini, Rahul Mallick, Petri Mäkinen, Seppo Ylä-Herttuala

{"title":"Insights into Prime Editing Technology: A Deep Dive into Fundamentals, Potentials, and Challenges.","authors":"Seyed Younes Hosseini, Rahul Mallick, Petri Mäkinen, Seppo Ylä-Herttuala","doi":"10.1089/hum.2024.043","DOIUrl":"10.1089/hum.2024.043","url":null,"abstract":"As the most versatile and precise gene editing technology, prime editing (PE) can establish a durable cure for most human genetic disorders. Several generations of PE have been developed based on an editor machine or prime editing guide RNA (pegRNA) to achieve any kind of genetic correction. However, due to the early stage of development, PE complex elements need to be optimized for more efficient editing. Smart optimization of editor proteins as well as pegRNA has been contemplated by many researchers, but the universal PE machine's current shortcomings remain to be solved. The modification of PE elements, fine-tuning of the host genes, manipulation of epigenetics, and blockage of immune responses could be used to reach more efficient PE. Moreover, the host factors involved in the PE process, such as repair and innate immune system genes, have not been determined, and PE cell context dependency is still poorly understood. Regarding the large size of the PE elements, delivery is a significant challenge and the development of a universal viral or nonviral platform is still far from complete. PE versions with shortened variants of reverse transcriptase are still too large to fit in common viral vectors. Overall, PE faces challenges in optimization for efficiency, high context dependency during the cell cycling, and delivery due to the large size of elements. In addition, immune responses, unpredictability of outcomes, and off-target effects further limit its application, making it essential to address these issues for broader use in nonpersonalized gene editing. Besides, due to the limited number of suitable animal models and computational modeling, the prediction of the PE process remains challenging. In this review, the fundamentals of PE, including generations, potential, optimization, delivery, in vivo barriers, and the future landscape of the technology are discussed.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"649-668"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237794","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}

引用次数: 0

An Improved Helper Plasmid Containing Deletions Within the E4 and E2a Genes Results in Increased Adeno-Associated Virus Productivity. 含有 E4 和 E2a 基因缺失的改良辅助质粒可提高 AAV 的产量。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-07-31 DOI: 10.1089/hum.2024.059

Laura van Lieshout, Stacy Ota, Annie Adusei, Eli Wiberg, Katrina Costa-Grant, Dimpal Lata, Serena Dollive, Marissa Stanvick, Ifeyinwa Iwuchukwu, Diane Golebiowski, Jin Yin

{"title":"An Improved Helper Plasmid Containing Deletions Within the E4 and E2a Genes Results in Increased Adeno-Associated Virus Productivity.","authors":"Laura van Lieshout, Stacy Ota, Annie Adusei, Eli Wiberg, Katrina Costa-Grant, Dimpal Lata, Serena Dollive, Marissa Stanvick, Ifeyinwa Iwuchukwu, Diane Golebiowski, Jin Yin","doi":"10.1089/hum.2024.059","DOIUrl":"10.1089/hum.2024.059","url":null,"abstract":"The use of a helper plasmid to replace adenovirus infection for adeno-associated virus (AAV) manufacturing has been common practice for decades. Adenovirus E4, E2a, and VA RNA genes are sufficient to support efficient AAV replication. In an effort to ensure that all transfected DNA has a functional role in AAV production, deletions were introduced to the E4 and E2a genes to determine if any portions were dispensable. Although a 900 bp deletion in the E2a intron did not have an impact, the removal of open reading frames (orf) 1-4 from the E4 gene resulted in a doubling of AAV productivity. The E4Δorf1-4 deletion was associated with a reduction in E4orf6 transcripts, along with an increase in Rep and Cap transcripts and protein levels, which corresponded to increased AAV productivity in crude lysate. The final product of these studies was a helper plasmid, termed OXB-Helper_3, that is >3.4 kb smaller than the original control plasmid and resulted in ∼2× improvement in vector genome productivity across multiple capsid serotypes, genome designs, and transfection platforms.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"767-776"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603564","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}

引用次数: 0

Inhalation of SP-101 Followed by Inhaled Doxorubicin Results in Robust and Durable hCFTRΔR Transgene Expression in the Airways of Wild-Type and Cystic Fibrosis Ferrets. 吸入 SP-101 后再吸入多柔比星，可在野生型和囊性纤维化雪貂的气道中产生强大而持久的 hCFTRΔR 转基因表达。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-09-04 DOI: 10.1089/hum.2024.064

Katherine J D A Excoffon, Mark D Smith, Lillian Falese, Robert Schulingkamp, Shen Lin, Madhu Mahankali, Poornima K L Narayan, Matthew R Glatfelter, Maria P Limberis, Eric Yuen, Roland Kolbeck

{"title":"Inhalation of SP-101 Followed by Inhaled Doxorubicin Results in Robust and Durable hCFTRΔR Transgene Expression in the Airways of Wild-Type and Cystic Fibrosis Ferrets.","authors":"Katherine J D A Excoffon, Mark D Smith, Lillian Falese, Robert Schulingkamp, Shen Lin, Madhu Mahankali, Poornima K L Narayan, Matthew R Glatfelter, Maria P Limberis, Eric Yuen, Roland Kolbeck","doi":"10.1089/hum.2024.064","DOIUrl":"10.1089/hum.2024.064","url":null,"abstract":"Cystic fibrosis (CF) is a serious genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approved small molecule therapies benefit the majority of people with CF (pwCF), but unfortunately not all. Gene addition offers a mutation agnostic treatment option for all pwCF. SP-101 is an adeno-associated virus gene therapy vector (AAV2.5T) that has been optimized for efficient human airway cell transduction, and that contains a functional and regulated shortened human CFTR minigene (hCFTRΔR) with a small synthetic promoter/enhancer. To understand SP-101 airway distribution, activity, and the associated immune response, in vivo studies were performed in wild-type and CF ferrets. After single dose inhaled delivery of SP-101, followed by single dose inhaled doxorubicin (an AAV transduction augmenter) or saline, SP-101 vector genomes were detected throughout the respiratory tract. hCFTRΔR mRNA expression was highest in ferrets also receiving doxorubicin and persisted for the duration of the study (13 weeks). Pre-existing mucus in the CF ferrets did not present a barrier to effective transduction. Binding and neutralizing antibodies to the AAV2.5T capsid were observed regardless of doxorubicin exposure. Only a portion of ferrets exhibited a weak T-cell response to AAV2.5T and no T-cell response was seen against hCFTRΔR. These data strongly support the continued development of inhaled SP-101, followed by inhaled doxorubicin, for the treatment of CF.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"710-725"},"PeriodicalIF":3.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999776","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}

引用次数: 0

The Legal Status and Improvement Path of Human Genetic Data in Gene Therapy in China. 中国人类基因数据在基因治疗中的法律地位和完善路径。

IF 3.9 3区医学

Human gene therapy Pub Date : 2024-08-01 Epub Date: 2024-07-31 DOI: 10.1089/hum.2024.097

Jiajv Chen, Wei Li

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