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Cell-Penetrating Peptides and CRISPR-Cas9: A Combined Strategy for Human Genetic Disease Therapy. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-09-14 Carla Lira,Eduardo Mannarino Correia,Martin Bonamino,Zilton Farias Meira Vasconcelos
The advent of Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated nuclease 9 (Cas9) technology has revolutionized the field of genetic engineering, offering unprecedented potential for the targeted manipulation of DNA sequences. Advances in the mechanism of action of the CRISPR-Cas9 system allowed potential applicability for the treatment of genetic diseases. CRISPR-Cas9's
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Adeno-Associated Virus Vectors-a Target of Cellular and Humoral Immunity-are Expanding Their Reach Toward Hematopoietic Stem Cell Modification and Immunotherapies. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-28 Angela E Araujo,Martin Bentler,Xabier Perez Garmendia,Asma Kaleem,Claire Fabian,Michael Morgan,Ulrich T Hacker,Hildegard Büning
All current market-approved gene therapy medical products for in vivo gene therapy of monogenic diseases rely on adeno-associated virus (AAV) vectors. Advances in gene editing technologies and vector engineering have expanded the spectrum of target cells and, thus, diseases that can be addressed. Consequently, AAV vectors are now being explored to modify cells of the hematopoietic system, including
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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. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-09-04 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
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
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SP-101, A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Cystic Fibrosis, Mediates Functional Correction of Primary Human Airway Epithelia From Donors with Cystic Fibrosis. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-29 Katherine Jda Excoffon,Shen Lin,Poornima Kotha Lakshmi Narayan,Sneha Sitaraman,Awal M Jimah,Tyler T Fallon,Melane L James,Matthew R Glatfelter,Maria P Limberis,Mark D Smith,Guia Guffanti,Roland Kolbeck
Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human CFTR minigene
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Gene Editing by Ferrying of CRISPR/Cas Ribonucleoprotein Complexes in Enveloped Virus-Derived Particles. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-27 Jacob Hørlück Janns,Jacob Giehm Mikkelsen
The invention of next-generation CRISPR/Cas gene editing tools, like base and prime editing, for correction of gene variants causing disease, has created hope for in vivo use in patients leading to wider clinical translation. To realize this potential, delivery vehicles that can ferry gene editing tool kits safely and effectively into specific cell populations or tissues are in great demand. In this
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Alpharetroviral Vector-Mediated Gene Therapy for IL7RA-Deficient Severe Combined Immunodeficiency. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-27 Teng-Cheong Ha,Michael A Morgan,Adrian J Thrasher,Axel Schambach
Severe combined immunodeficiency (SCID) encompasses rare primary immunodeficiency disorders characterized by deficient T-cell development, which leads to a severely compromised immune system and susceptibility to life-threatening infections. Among SCID subtypes, IL7RA-SCID is caused by mutations in the interleukin 7 receptor alpha chain (IL7RA) and represents a significant subset of patients with limited
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Advances in MicroRNA Therapeutics: from Preclinical to Clinical Studies. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-16 Simona Brillante,Mariagrazia Volpe,Alessia Indrieri
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
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Lipid Nanoparticles for Nucleic Acid Delivery Beyond the Liver. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-28 Nadine Saber,Mariona Estapé Senti,Raymond M Schiffelers
Lipid nanoparticles (LNPs) are the most clinically advanced drug delivery system for nucleic acid therapeutics, exemplified by the success of the COVID-19 mRNA vaccines. However, their clinical use is currently limited to hepatic diseases and vaccines due to their tendency to accumulate in the liver upon intravenous administration. To fully leverage their potential, it is essential to understand and
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Gene Editing of the Endogenous Cryptic 3' Splice Site Corrects the RNA Splicing Defect in the β654-Thalassemia Mouse Model. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-13 Dan Lu,Xiuli Gong,Xinbing Guo,Qin Cai,Yanwen Chen,Yiwen Zhu,Xiao Sang,Hua Yang,Miao Xu,Yitao Zeng,Dali Li,Fanyi Zeng
β654-thalassemia is caused by a point mutation in the second intron (IVS-II) of the β-globin gene that activates a cryptic 3' splice site, leading to incorrect RNA splicing. Our previous study demonstrated that when direct deletion of the β654 mutation sequence or the cryptic 3' splice site in the IVS-II occurs, correct splicing of β-globin mRNA can be restored. Herein, we conducted an in-depth analysis
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Modulation of AAV9 Galactose Binding Yields Novel Gene Therapy Vectors and Predicts Cross-Species Differences in Glycan Avidity. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-13 Jacob A Hoffman,Nathan Denton,Joshua J Sims,Rosemary Meggersee,Zhe Zhang,Kanyin Olagbegi,James M Wilson
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
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Intra-Articular Delivery of an AAV-Anti-TNF-α Vector Alleviates the Progress of Arthritis in a RA Mouse Model. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-12 Xiao Ke,Qing Xie,Shuang Luo,Qingwei Li,Qiang Zheng,Zhirong Zhang
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease marked by joint destruction and functional impairment. Tumor necrosis factor (TNF) plays a critical role in RA pathogenesis. Although TNF-targeting drugs are clinically effective, their need for frequent and long-term administration often results in poor patient adherence and suboptimal outcomes. This study developed a gene therapy
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Lipid Nanoparticle mRNA Therapy Improves Survival and Reduces Serum Branched-Chain Amino Acids in Mouse Models of Maple Syrup Urine Disease. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-05 Jenny A Greig,Matthew Jennis,Aditya Dandekar,Joanna K Chorazeczewski,Nesteene Param,Meardey So,Mohamad Nayal,Peter Bell,Kimberly Coughlan,Minjung Choi,Paloma H Giangrande,Paolo G V Martini,James M Wilson
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Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-02 Yi Zhou,Yongzhong Li,Jing Chenm,Kai Mei,Mingxiang Kang,Ping Chen,Qiu Li
A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities
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Roche, Ascidian Launch Up-to-$1.8B RNA Exon Editing Collaboration. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-01 Alex Philippidis
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Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-01 Jan C Klapwijk,Alberto Del Rio Espinola,Silvana Libertini,Philippe Collin,Mick D Fellows,Susan Jobling,Anthony M Lynch,HansJoerg Martus,Catherine Vickers,Andreas Zeller,Luca Biasco,Martijn H Brugman,Frederic D Bushmann,Toni Cathomen,Hildegrund C J Ertl,Richard Gabriel,Guangping Gao,Julie K Jadlowsky,Ian Kimber,Thomas A Lanz,Bruce L Levine,Kenneth P Micklethwaite,Masafumi Onodera,Daniella M Pizzurro
Regulators and industry are actively seeking improvements and alternatives to current models and approaches to evaluate potential carcinogenicity of gene therapies (GTs). A meeting of invited experts was organized by NC3Rs/UKEMS (London, March 2023) to discuss this topic. This article describes the consensus reached among delegates on the definition of vector genotoxicity, sources of uncertainty, suitable
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Genome Editing of Mammalian Cells Through RNA Transcript-Mediated Homologous Recombination Repair. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-08-01 Yangmin Wang,Meilin Liu,Xinjian Lin,Haozheng Wang,Na Dong,Hengshen Liu,Hongwei Shao,Wenfeng Zhang
Double-stranded break (DSB) repair of eukaryotic DNA is mainly accomplished by nonhomologous end joining and homologous recombination (HR). Providing exogenous templates during HR repair can result in the editing of target genes, which is the central mechanism of the well-established clustered regularly interspaced short palindromic repeats (CRISPR) gene editing system. Currently, exogenous templates
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An Improved Helper Plasmid Containing Deletions Within the E4 and E2a Genes Results in Increased Adeno-Associated Virus Productivity. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-31 Laura van Lieshout,Stacy Ota,Annie Adusei,Eli Wiberg,Katrina Costa-Grant,Dimpal Lata,Serena Dollive,Marissa Stanvick,Ifeyinwa Iwuchukwu,Diane Golebiowski,Jin Yin
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
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The Legal Status and Improvement Path of Human Genetic Data in Gene Therapy in China. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-31 Jiajv Chen,Wei Li
In the legal context of Chinese law, genetic data are an object of complex rights. At the level of private law, genetic data contain personal information, thus being protected by the Civil Code and the Personal Information Protection Law. At the level of public law, genetic data are important genetic resource that embody both public and national interests, which should also be regulated by public laws
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An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-27 Robert E MacLaren,Isabelle Audo,M Dominik Fischer,Rachel M Huckfeldt,Byron L Lam,Mark E Pennesi,Robert Sisk,James A Gow,Jiang Li,Kan Zhu,So-Fai Tsang
Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov).
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Developing Gene Therapy for Mitigating Multisystemic Pathology in Fabry Disease: Proof of Concept in an Aggravated Mouse Model. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-22 Natalia Boukharov,Shipeng Yuan,Wanida Ruangsirluk,Saravanan Ayyadurai,Ashiqur Rahman,Melody Rivera-Hernandez,Shashank Sunkara,Kristin Tonini,Eric Y H Park,Mugdha Deshpande,Rizwana Islam
Fabry disease (FD) is a multisystemic lysosomal storage disorder caused by the loss of α-galactosidase A (α-Gal) function. The current standard of care, enzyme replacement therapies, while effective in reducing kidney pathology when treated early, do not fully ameliorate cardiac issues, neuropathic manifestations, and risk of cerebrovascular events. Adeno-associated virus (AAV)-based gene therapies
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Have a Little Heart (or Not): Highly Minimized Skeletal Muscle Regulatory Cassettes with Low or No Activity in the Heart. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-19 Charis L Himeda,Takako I Jones,Peter L Jones
Adeno-associated virus-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression
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Boy Dosed with Pfizer's Duchenne Muscular Dystrophy Gene Therapy Dies a Year After Phase II Trial. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-09 Alex Philippidis
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Innate Immune Sensing of Adeno-Associated Virus Vectors. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-05 Di Cao,Barry J Byrne,Ype P de Jong,Cox Terhorst,Dongsheng Duan,Roland W Herzog,Sandeep R P Kumar
Adeno-associated virus (AAV) based viral vectors are widely used in human gene therapy and form the basis of approved treatments for several genetic diseases. Immune responses to vector and transgene products, however, substantially complicate these applications in clinical practice. The role of innate immune recognition of AAV vectors was initially unclear, given that inflammatory responses early
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Gene Coexpression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-04 Jason C Huang,Ming-Chun Li,I-Chieh Huang,Je-Ming Hu,Wei-Zhi Lin,Yu-Tien Chang
Early diagnosis and intervention are pivotal in reducing colorectal cancer (CRC) incidence and enhancing patient outcomes. In this study, we focused on three genes, AQP8, GUCA2B, and SPIB, which exhibit high coexpression and play crucial roles in suppressing early-stage CRC. Our objective was to identify key miRNAs that can mitigate CRC tumorigenesis and modulate the coexpression network involving
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AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-03 Shun-Qing Liang,Andrew W Navia,Michelle Ramseier,Xuntao Zhou,Michele Martinez,Charles Lee,Chen Zhou,Joae Wu,Jun Xie,Qin Su,Dan Wang,Terence R Flotte,Daniel G Anderson,Alice F Tarantal,Alex K Shalek,Guangping Gao,Wen Xue
Genome editing has the potential to treat genetic diseases in a variety of tissues, including the lung. We have previously developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing in the airways of mice. To validate this delivery vehicle in a large animal model, we have shown that intratracheal instillation of CRISPR/Cas9 in AAV5 can edit a housekeeping
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Pfizer Weighs Next Steps after DMD Therapy Linked to Boy's Death Fails Phase III Trial. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-01 Alex Philippidis
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Insights into Prime Editing Technology: A Deep Dive into Fundamentals, Potentials, and Challenges. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-07-01 Seyed Younes Hosseini,Rahul Mallick,Petri Mäkinen,Seppo Ylä-Herttuala
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
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Methodological Validation of Sedimentation Velocity Analytical Ultracentrifugation Method for Adeno-Associated Virus and Collaborative Calibration of System Suitability Substance. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-06-11 Xi Qin,Qikun Yu,Xiang Li,Wei Jiang,Xinchang Shi,Wenxiu Hou,Da Zhang,Zhenzhen Cai,Hua Bi,Wenhong Fan,Youxue Ding,Yichen Yang,Biao Dong,Long Chen,Dehua Huo,Cong Wang,Yong Zhou,Dening Pei,Miao Ye,Chenggang Liang
Currently, adeno-associated virus (AAV) is one of the primary gene delivery vectors in gene therapy, facilitating long-term in vivo gene expression. Despite being imperative, it is incredibly challenging to precisely assess AAV particle distribution according to the sedimentation coefficient and identify impurities related to capsid structures. This study performed the systematic methodological validation
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CRISPR-Cas Genome Editing in Ex Vivo Human Lungs to Rewire the Translational Path of Genome-Targeting Therapeutics. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-05-23 Kumi Mesaki,Haruchika Yamamoto,Stephen Juvet,Jonathan Yeung,Zehong Guan,Akhi Akhter,Yan Yao,Cameron Dickie,Henna Mangat,Aizhou Wang,Gavin W Wilson,Andrea Mariscal,Jim Hu,Alan R Davidson,Benjamin P Kleinstiver,Marcelo Cypel,Mingyao Liu,Shaf Keshavjee
The ongoing advancements in CRISPR-Cas technologies can significantly accelerate the preclinical development of both in vivo and ex vivo organ genome-editing therapeutics. One of the promising applications is to genetically modify donor organs prior to implantation. The implantation of optimized donor organs with long-lasting immunomodulatory capacity holds promise for reducing the need for lifelong
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Advances in Bone-Targeting Drug Delivery: Emerging Strategies Using Adeno-Associated Virus. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-05-03 Tadatoshi Sato,Sachin Chaugule,Matthew B Greenblatt,Guangping Gao,Jae-Hyuck Shim
The development of bone-targeting drug delivery systems holds immense promise for improving the treatment of skeletal diseases. By precisely delivering therapeutic agents to the affected areas of bone, these strategies can enhance drug efficacy, minimize off-target effects, and promote patient adherence, ultimately leading to improved treatment outcomes and an enhanced quality of life for patients
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Verve Pauses Enrollment in Base Editing Trial after Adverse Events. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-05-01 Alex Philippidis
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Intravitreal Delivery of rAAV2-hSyn-hRS1 Results in Retinal Ganglion Cell-Specific Gene Expression and Retinal Improvement in the Rs1-KO Mouse. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-05-01 Yangyang Zheng,Xin Xu,Ruoyue Fan,Haolang Jiang,Qingguo Guo,Xuefei Han,Ying Liu,Guangzuo Luo
X-linked retinoschisis (XLRS) is a monogenic recessive inherited retinal disease caused by defects in retinoschisin (RS1). It manifests clinically as retinal schisis cavities and a disproportionate reduction of b-wave amplitude compared with the a-wave amplitude. Currently there is no approved treatment. In the last decade, there has been major progress in the development of gene therapy for XLRS.
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Role of FoxP3+ Regulatory T Cells in Modulating Immune Responses to Adeno-Associated Virus Gene Therapy. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-04-11 Maite Muñoz-Melero,Moanaro Biswas
Adeno-associated virus (AAV) gene therapy is making rapid strides owing to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to
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A Review of the Cost-Effectiveness Evidence for FDA-Approved Cell and Gene Therapies. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-04-09 Sumaya Abuloha,Shu Niu,Darlene Adirika,Benjamin P Harvey,Mikael Svensson
Cell and gene therapy (CGT) innovations have provided several significant breakthroughs in recent years. However, CGTs often come with a high upfront cost, raising questions about patient access, affordability, and long-term value. This study reviewed cost-effectiveness analysis (CEA) studies that have attempted to assess the long-term value of Food and Drug Administration (FDA)-approved CGTs. Two
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Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-04-08 Chujiao Lin,Matthew B Greenblatt,Guangping Gao,Jae-Hyuck Shim
Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low postinfection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations
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Orchard Therapeutics Gains First U.S. Approval for a Metachromatic Leukodystrophy Gene Therapy. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-04-01 Alex Philippidis
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Pre-Existing Immunity to a Nucleic Acid Contaminant-Derived Antigen Mediates Transaminitis and Resultant Diminished Transgene Expression in a Mouse Model of Hepatic Recombinant Adeno-Associated Virus-Mediated Gene Transfer. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-28 Mark A Brimble,Christopher L Morton,Stephen M Winston,Isaiah L Reeves,Yunyu Spence,Pei-Hsin Cheng,Junfang Zhou,Amit C Nathwani,Paul G Thomas,Aisha Souquette,Andrew M Davidoff
Liver injury with concomitant loss of therapeutic transgene expression can be a clinical sequela of systemic administration of recombinant adeno-associated virus (rAAV) when used for gene therapy, and a significant barrier to treatment efficacy. Despite this, it has been difficult to replicate this phenotype in preclinical models, thereby limiting the field's ability to systematically investigate underlying
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Complement System Response to Adeno-Associated Virus Vector Gene Therapy. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-18 Elizabeth Kropf,David M Markusic,Anna Majowicz,Federico Mingozzi,Klaudia Kuranda
Adeno-associated virus (AAV) vectors represent a novel tool for the delivery of genetic therapeutics and enable the treatment of a wide range of diseases. Success of this new modality is challenged, however, by cases of immune-related toxicities that complicate the clinical management of patients and potentially limit the therapeutic efficacy of AAV gene therapy. While significant progress has been
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The New Frontiers of Gene Therapy and Gene Editing in Inflammatory Diseases. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-12 Alessandro Romano,Alessandra Mortellaro
Inflammatory diseases are conditions characterized by abnormal and often excessive immune responses, leading to tissue and organ inflammation. The complexity of these disorders arises from the intricate interplay of genetic factors and immune responses, which challenges conventional therapeutic approaches. However, the field of genetic manipulation has sparked unprecedented optimism in addressing these
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Kenneth I. Berns, MD, PhD [1938-2024]. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Barry J Byrne,Terence R Flotte,Roland W Herzog,Arun Srivastava
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Akouos Therapy Restores 11-Year-Old Boy's Hearing After 1 Month. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Alex Philippidis
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Combination Immunotherapy of Oncolytic Flu-Vectored Virus and Programmed Cell Death 1 Blockade Enhances Antitumor Activity in Hepatocellular Carcinoma. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Hongyu Yu,Fang Sun,Yan Xu,Hao Yang,Chongyu Tian,Cong Li,Yimin Kang,Lei Hao,Penghui Yang
Oncolytic viruses (OVs) are appealing anti-tumor agents. But it is limited in its effectiveness. In this study, we used combination therapy with immune checkpoint inhibitor to enhance the antitumor efficacy of OVs. Using reverse genetics technology, we rescued an oncolytic influenza virus with the name delNS1-GM-CSF from the virus. After identifying the hemagglutination and 50% tissue culture infectivedose
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Current Status and Prospects of Viral Vector-Based Gene Therapy to Treat Kidney Diseases. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Louise Medaer,Koenraad Veys,Rik Gijsbers
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
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Gutless Helper-Dependent and First-Generation HAdV5 Vectors Have Similar Mechanical Properties and Common Transduction Mechanisms. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Lars Thalmann,Natalia Martin-Gonzalez,Dominik Brücher,Andreas Plückthun,Pedro J de Pablo,Maarit Suomalainen,Urs F Greber
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
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Therapeutic Strategy for Fabry Disease by Intravenous Administration of Adeno-Associated Virus 9 in a Symptomatic Mouse Model. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Yuka Hayashi,Yoshihide Sehara,Ryota Watano,Kenji Ohba,Yuki Takayanagi,Yoshio Sakiyama,Kazuhiro Muramatsu,Hiroaki Mizukami
Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A), an enzyme that hydrolyzes glycosphingolipids in lysosome. Accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in tissues, induces cellular dysfunction leading to multi-organ disorder. Gene therapy is a promising strategy that can overcome these problems, and virus vectors
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Knockout and Replacement Gene Surgery to Treat Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-03-01 Xuehan Sun,Chen Liang,Yangcan Chen,Tongtong Cui,Jiabao Han,Moyu Dai,Ying Zhang,Qi Zhou,Wei Li
Mutations in the rhodopsin (RHO) gene are the predominant causes of autosomal dominant retinitis pigmentosa (adRP). Given the diverse gain-of-function mutations, therapeutic strategies targeting specific sequences face significant challenges. Here, we provide a universal approach to conquer this problem: we have devised a CRISPR-Cas12i-based, mutation-independent gene knockout and replacement compound
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Development of an Enzyme-Linked Immunosorbent Spot Assay for the Assessment of Adeno-Associated Virus Peptides to Examine Immune Safety. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-22 Sara Rose Krivoshik,Lindsey Dzielak,April R Masters,Jennifer Hall,Alison J Johnson
Adeno-associated virus (AAV)-based gene therapies have shown promise as novel treatments for rare genetic disorders such as hemophilia A and spinal muscular atrophy. However, cellular immune responses mediated by cytotoxic (CD8+) and helper (CD4+) T cells may target vector-transduced cells as well as healthy immune cells, impacting safety and efficacy. In this study, we describe the optimization and
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Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-06 Zeyu Han,Xianyanling Yi,Jin Li,Dazhou Liao,Guangping Gao,Jianzhong Ai
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
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Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-06 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
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
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Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-02 Fabio Catalano,Eva C Vlaar,Zina Dammou,Drosos Katsavelis,Tessa F Huizer,Giacomo Zundo,Marianne Hoogeveen-Westerveld,Esmeralda Oussoren,Hannerieke J M P van den Hout,Gerben Schaaf,Karin Pike-Overzet,Frank J T Staal,Ans T van der Ploeg,W W M Pim Pijnappel
Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing
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A Paradox of the Field's Own Success: Unintended Challenges in Bringing Cutting-Edge Science from the Bench to the Market. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-01 Nathan Yingling,Miguel Sena-Esteves,Heather L Gray-Edwards
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Adeno-Associated Virus Type 9-Mediated Gene Therapy of Choline Acetyltransferase-Deficient Mice. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-02-01 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
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 (CHAT) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for Chat (Chat-/-) die at birth. To circumvent the
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Ex Vivo Gene Therapy in Organ Transplantation: Considerations and Clinical Translation. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-30 Michelle Mendiola Pla,Dawn E Bowles
Ex vivo machine perfusion (EVMP) is rapidly growing in utility during solid organ transplantation. This form of organ preservation is transforming how organs are allocated and expanding the definition of what is considered a suitable organ for transplantation in comparison with traditional static cold storage. All major organs (heart, lung, liver, kidney) have been influenced by this advanced method
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Concise Analysis of Single-Stranded DNA of Recombinant Adeno-Associated Virus By Automated Electrophoresis System. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-30 Yuzhe Yuan,Kiyoko Higashiyama,Noriko Hashiba,Kyoko Masumi-Koizumi,Keisuke Yusa,Kazuhisa Uchida
Recombinant adeno-associated virus (rAAV) is a prominent viral vector currently available for human gene therapy. The diameter of the rAAV capsid is ∼25 nm, and a positive or negative single-stranded DNA is packaged within the vector capsid. In this report, we describe a concise method to examine the extracted rAAV genome using an automated electrophoresis system. The rAAV genome, prepared from vector
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Multidimensional Response Surface Methodology for the Development of a Gene Editing Protocol for p67phox-Deficient Chronic Granulomatous Disease. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-24 Thomas E Whittaker,Shefta E Moula,Sameer Bahal,Faris Ghalib Bakri,Wail Ahmad Hayajneh,Ammar Khaled Daoud,Asma Naseem,Alessia Cavazza,Adrian J Thrasher,Giorgia Santilli
Replacing a faulty gene with a correct copy has become a viable therapeutic option as a result of recent progress in gene editing protocols. Targeted integration of therapeutic genes in hematopoietic stem cells has been achieved for multiple genes using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system and Adeno-Associated Virus (AAV) to carry a donor template. Although
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Leveraging CRISPR-Cas9 for Accurate Detection of AAV-Neutralizing Antibodies: The AAV-HDR Method. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-19 Guohua Li,Saining Tian,Xinyu Sun,Mei Zhao,Feng Zhang,Jian-Ping Zhang,Tao Cheng,Xiao-Bing Zhang
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CASGEVY Makes History as FDA Approves First CRISPR/Cas9 Genome Edited Therapy. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-01 Alex Philippidis
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Prophylactic Prednisolone Promotes AAV5 Hepatocyte Transduction Through the Novel Mechanism of AAV5 Coreceptor Platelet-Derived Growth Factor Receptor Alpha Upregulation and Innate Immune Suppression. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-01 Britta Handyside,Lening Zhang,Bridget Yates,Lin Xie,Ashrafali Mohamed Ismail,Ryan Murphy,Brian Baridon,Cheng Su,Taren Bouwman,Linley Mangini,Jorden Tahquechi,Sandra Salcido,Wesley C Minto,William T Keenan,Ioanna Ntai,Choong-Ryoul Sihn,Sherry Bullens,Stuart Bunting,Sylvia Fong
Adeno-associated virus (AAV) vectors are used to deliver therapeutic transgenes, but host immune responses may interfere with transduction and transgene expression. We evaluated prophylactic corticosteroid treatment on AAV5-mediated expression in liver tissue. Wild-type C57BL/6 mice received 6 × 1013 vg/kg AAV5-HLP-hA1AT, an AAV5 vector carrying a human α1-antitrypsin (hA1AT) gene with a hepatocyte-specific
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A Novel Role for the Adenovirus L4 Region 22K and 33K Proteins in Adeno-Associated Virus Production. Hum. Gene Ther. (IF 3.9) Pub Date : 2024-01-01 Angela Adsero,Brendan Chestnut,Sara Shahnejat-Bushehri,Lalita Sasnoor,Travis McMurphy,Mike Swenor,Ryan Pasquino,Arun Pradhan,Victor Hernandez,Linas Padegimas,David Dismuke
Despite decades of research in adeno-associated virus (AAV) and the role of adenovirus in production, the interplay of AAV and adenovirus is not fully understood. Specific regions of the adenoviral genome containing E1, E2a, E4 open reading frame (ORF), and VA RNA have been demonstrated as necessary for AAV production; however, incorporating these regions into either a producer cell line or subcloning