Human gene therapy最新文献

{"title":"Effective Treatment of Colq-Deficient Mice with Adeno-Associated Virus Type Rh74-Mediated Gene Therapy.","authors":"Abigail McInnes, Jaime N Young, Anahid S Aivazian, Kyley Linn, Marc A Gonzalez, Sarah E Cook, Jessica Vazquez, Claudia Canzonetta, Patricio V Sepulveda S, Ricardo A Maselli","doi":"10.1177/10430342251386011","DOIUrl":"https://doi.org/10.1177/10430342251386011","url":null,"abstract":"<p><p>Mutations in human <i>COLQ</i>, which encodes the collagen-like tail subunit (ColQ) of asymmetrical acetylcholinesterase (AChE), cause congenital myasthenic syndrome (CMS) with deficiency of end plate AChE. A valuable animal model of <i>COLQ</i>-CMS is the Colq-deficient (<i>Colq^-/-</i>) mouse, which lacks asymmetrical AChE in skeletal and cardiac muscles. Mutant <i>Colq^-/-</i> mice fail to thrive, and many die before reaching maturity. With the aim of developing a treatment for <i>COLQ</i>-CMS, <i>Colq^-/-</i> mice were injected at postnatal day 26-29 with three doses of an adeno-associated virus type rh74 carrying full-length human <i>COLQ</i> (AAVrh74-<i>COLQ</i>): 5 × 10¹³ viral genomes per kilogram (vg/kg) (intravenously [IV]), 1 × 10¹⁴ vg/kg (IV), and 2 × 10¹⁴ vg/kg (1 × 10¹⁴ vg/kg IV + 1 × 10¹⁴ vg/kg intraperitoneally). Motor performance was evaluated using rotarod, grip strength, and wire hang tests weekly for 12 weeks. Voluntary ambulation and repetitive nerve stimulation (RNS) were assessed once before euthanasia. Protein and RNA expression of COLQ was measured via immunohistochemistry (IHC) and reverse transcriptase quantitative PCR (RT-qPCR), respectively. Mice treated with AAVrh74-<i>COLQ</i> at 1 × 10¹⁴ and 2 × 10¹⁴ vg/kg doses showed 100% survival and no adverse side effects. Mice injected with 2 × 10¹⁴ vg/kg showed almost full recovery and similar scores to wild type that were significantly higher than vehicle-injected mutants for grip strength (<i>p</i> value <0.0001), rotarod (<i>p</i> value <0.0001), and RNS (<i>p</i> value <0.0001). Similar improvements were observed in mice injected with 1 × 10¹⁴ vg/kg, although the recovery of grip strength was incomplete. Mice injected with 5 × 10¹³ vg/kg showed incomplete recovery. IHC demonstrated full recovery of protein expression in 1 × 10¹⁴ and 2 × 10¹⁴ vg/kg mice, and RT-qPCR unambiguously demonstrated that the source of the ColQ was human <i>COLQ.</i> In summary, a single treatment of AAVrh74-<i>COLQ</i> (1 × 10¹⁴ to 2 × 10¹⁴ vg/kg) was effective and safe for <i>Colq</i>^-/-mice, which reproduce many of the clinical features of the human <i>COLQ</i>-CMS phenotype. Thus, these results support a similar therapy for patients affected with <i>COLQ</i>-CMS.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244349","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":"Interview with Serena Scala, PhD.","authors":"","doi":"10.1177/10430342251383877","DOIUrl":"https://doi.org/10.1177/10430342251383877","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185815","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":"SNAC: A Single-Nuclei Atlas of Capsid Distribution in Nonhuman Primate Eye.","authors":"Rachna Manek, Eugenia Lyashenko, Andre H Kurlovs, Yinyin Huang, Jeremy Huang, Margaret Hennessy, Jason Wu, Jasmine Bloom, Tess Torregrosa, Edith L Pfister, Pavitra Ramachandran, Virginia Savova, Christian Mueller, Giorgio Gaglia, Sourav R Choudhury","doi":"10.1177/10430342251382510","DOIUrl":"https://doi.org/10.1177/10430342251382510","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) vectors have emerged as the leading gene therapy vehicle due to their favorable safety profile and sustained payload expression. Approved therapies such as voretigene neparvovec (Luxturna) and omnasemnogene abeparvovec (Zolgensma) rely on the tropism of natural AAV variants. The majority of discovered natural AAVs and engineered AAV capsids have not been comprehensively profiled for their biodistribution, especially at single-cell resolution. Recent advances in single nuclei sequencing can enable further refinement of AAV cell-type specificity and reduce off-target effects. However, low levels of transduction and muted sensitivity of current single-cell detection methods make screening pooled capsids at single-cell resolution challenging. Here, we develop SNAC (Single-Nuclei Atlas of Capsid distribution), an improved method for single-nuclei profiling of AAV transduction at multiplex scale. We provide proof of concept using the nonhuman primate eye as a model system, showing that we can accurately identify and quantify vector expression in all major retinal cell types. Furthermore, the ranking of capsids by SNAC agrees with that from pre-established tissue sampling protocols. Our method promises to reduce the time, effort, and cost of accurate cell-type-specific profiling of AAV capsids.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149012","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":"Pre-Existing Anti-Adeno-Associated Virus Immunity in Gene Therapy: Mechanisms, Challenges, and Potential Solutions.","authors":"Godwin I Iroanya, Pradeep N Subramanyam, Kevin D Wells, Jonathan A Green","doi":"10.1177/10430342251378524","DOIUrl":"https://doi.org/10.1177/10430342251378524","url":null,"abstract":"<p><p>Adeno-associated virus (AAV) vectors have emerged as versatile and promising tools in gene therapy due to their favorable safety profile, broad tissue tropism, and long-term gene expression. However, pre-existing immunity, especially in the form of neutralizing antibodies (NAbs) remains a significant barrier, reducing vector efficacy and restricting patient eligibility. This review provides a comprehensive overview of the immunological landscape affecting AAV gene therapy, including global seroprevalence, environmental influences, and antibody cross-reactivity stemming from natural parvovirus exposure or vaccination of animal research models.We detail the mechanisms underlying immune detection and vector clearance, covering innate pattern recognition receptors, complement activation, and adaptive immune effector functions such as antibody-dependent complement deposition, cytotoxicity, and phagocytosis.We further analyze how species, age, serotype, administration route, and target tissue contribute to immune susceptibility and variable transduction outcomes. To overcome these challenges, we propose a three-pronged classification of mitigation strategies: (1) immune-focused strategies, such as plasmapheresis, immunoadsorption, enzymatic antibody cleavage, corticosteroids, and B cell depletion; (2) delivery-focused strategies, which include targeting immune-privileged sites, localized or intrathecal delivery, and timing of vector administration; and (3) capsid-focused strategies, comprising rational capsid engineering and the use of decoy particles or empty capsids.We also discuss promising advances such as AAV-specific regulatory T cells and re-dosable AAV platforms. This strategic framework offers a roadmap for tailoring gene therapy approaches to individual immune profiles and improving the safety, efficacy, and accessibility of AAVbased therapeutics.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124574","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":"Update on Gene Therapy Clinical Trials for Eye Diseases.","authors":"Nicolas Lonfat, Laura Moreno-Leon, Claudio Punzo, Hemant Khanna","doi":"10.1177/10430342251379824","DOIUrl":"https://doi.org/10.1177/10430342251379824","url":null,"abstract":"<p><p>Inherited and complex retinal degenerative diseases, such as retinitis pigmentosa, age-related macular degeneration, and glaucoma, represent a significant global burden of irreversible vision loss. Due to immense genetic and clinical heterogeneity and complex underlying mechanisms, these diseases still lack safe and effective disease-modifying treatments. This review summarizes the current landscape of gene therapeutic approaches to develop novel treatments for these blinding conditions. Specifically, we provide an update on several ongoing or completed clinical trials on gene-specific or gene-agnostic approaches, including recombinant adeno-associated viral vector-mediated delivery of the full gene or gene editing and antisense oligonucleotide components into the eye. We also discuss the initial clinical trial results of the use of the different approaches to ocular delivery, including subretinal, intravitreal, and suprachoroidal delivery. While long-term clinical trial data and refined clinical endpoints are essential to assess the efficacy, safety, and durability of these strategies, the data so far underscore the immense potential of gene therapy to revolutionize the management of retinal diseases in patients living with these debilitating conditions.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080448","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":"Vertex, Enlaza Launch Up-to-$2B Collaboration to Improve CASGEVY® Conditioning.","authors":"Alex Philippidis","doi":"10.1177/10430342251382168","DOIUrl":"https://doi.org/10.1177/10430342251382168","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075245","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":"Lentiviral Gene Delivery Rescues Ciliary Defects in Patient-Derived Airway Organoids from Primary Ciliary Dyskinesia.","authors":"Chunxiao Huo, Ting Luo, Lei Wu, Feng Yang, Zhangqi Xu, Xiaofen Tao, Junhua Xia, Tianhua Zhou, Yuan Jiang, Shanshan Xie","doi":"10.1177/10430342251378128","DOIUrl":"10.1177/10430342251378128","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by defective ciliary motility, leading to recurrent respiratory infections and chronic airway damage. Gene therapy holds promise for treating PCD, but its effectiveness in patient-derived models remains uncertain. This study aimed to evaluate the therapeutic potential of lentiviral gene delivery in restoring ciliary function in patient-derived nasal apical-out airway organoids. Using nasal epithelial cells from both healthy individuals and PCD patients with mutations in <i>DNAAF1</i>, <i>DNAAF3</i>, or <i>DNAAF6</i>, we established organoid models to assess gene therapy efficacy. Lentiviral vectors successfully restored the expression and proper localization of DNAAF proteins in mutant organoids, significantly improving ciliary beating frequency and the proportion of organoids with functional cilia. These findings provide proof-of-concept evidence supporting gene therapy as a viable approach to correct ciliary defects in PCD, paving the way for targeted treatments.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064755","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":"Preclinical Assessment of Antibody Responses to Adeno-Associated Virus (AAV) Vector-Based Capsids of AAV2, AAV5, AAV8, or AAV9 in Laboratory Cynomolgus Macaques (<i>Macaca fascicularis</i>) of Asian or Mauritian Origin.","authors":"Betina Pajaziti, Ulf Michgehl, Dragica Blazevic, Franziska Fimm-Todt, Alexandra Duetting, Birgit Korbmacher, Stephanie Grote-Wessels, Stefan Michelfelder, Lars Mecklenburg","doi":"10.1177/10430342251376043","DOIUrl":"10.1177/10430342251376043","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based vectors are the most commonly used vectors for gene therapy. Wild-type AAV infections occur widely in humans and nonhuman primates (NHPs), and an accurate assessment of preexisting AAV antibodies is crucial for the efficient use of AAV-based gene therapies in preclinical and clinical studies. Cynomolgus macaques (<i>Macaca fascicularis</i>) are well-established preclinical large animal models for evaluating the efficacy and safety of AAV-mediated gene therapies intended for human use. We provide a retrospective evaluation comparing preexisting AAV-neutralizing or total antibody titers against serotypes AAV2, AAV5, AAV8, or AAV9 in cynomolgus macaque cohorts of Asian or Mauritian origin. We used an <i>in vitro</i> neutralizing antibody (NAB) assay to detect NAB titers or an <i>in vitro</i> Meso Scale Discovery-based assay for the quantification of total binding antibodies (TABs) in blood samples. Results were obtained to measure the serostatus of animals. In our analysis, the <i>in vitro</i> NAB assay revealed the lowest seroprevalence for AAV5 (13 ± 15% to 21 ± 6%) independent of origin. In the same assay, Asian animals were highly seropositive against AAV8, followed by AAV2 and AAV9 serotypes (88 ± 13%, 71 ± 10%, 69 ± 9%, respectively). Whereby, the prevalence of seropositivity was lower in animals of Mauritian origin with the highest seroprevalence for AAV9 (58 ± 7%), followed by AAV8 (53 ± 17%) and AAV2 (51 ± 20%) assessed by <i>in vitro</i> TAB assay. Notably, co-prevalences of antibody responses against AAV2, AAV8, and AAV9 serotypes resulted in 39.8% seropositivity (<i>in vitro</i> NAB assay) in NHPs of Asian and in about 32.6% (<i>in vitro</i> TAB assay) of Mauritian origin.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052957","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":"Safe and Efficacious Permanent Removal of Large COL7A1 Exons for Gene Reframing as a Reliable Therapeutic Strategy for Recessive Dystrophic Epidermolysis Bullosa.","authors":"Sergio López-Manzaneda, Ángeles Mencía, José Bonafont, Alex Bassons-Bascuñana, Marta García, Alexander Nyström, Blanca Duarte, Sara Llames, Rodolfo Murillas, Silvia Modamio-Hoybjor, Matías Morín, Lucía Soletto, María J Escamez, Miguel A Moreno-Pelayo, Marcela Del Rio, Fernando Larcher","doi":"10.1089/hum.2024.238","DOIUrl":"10.1089/hum.2024.238","url":null,"abstract":"<p><p>Mutations leading to premature termination codons in <i>COL7A1</i> are commonly associated with severe generalized recessive dystrophic epidermolysis bullosa (RDEB). Previous research, including our own, has indicated that removing mutated <i>COL7A1</i> exons along with the consequent reframing of <i>COL7A1</i> may not pose noticeable impact on protein function, offering a potential therapeutic strategy. However, investigations into the long-term <i>in vivo</i> effects of genome editing-mediated removal of mutant exons have only focused on the small exon 80 thus far. Hence, this study focuses on exons 73 and 105 of <i>COL7A1</i> to explore whether targeted exon removal, through a CRISPR/Cas9-assisted, Non-homologous end joining (NHEJ)-mediated approach, could be extended to other larger exons. Introducing ribonucleoprotein complexes carrying Cas9 and optimized sgRNA guide pairs for each exon (73 and 105) through electroporation efficiently led to their removal, consequently restoring type VII collagen (C7) synthesis in RDEB primary patient cells carrying frameshift mutations in these exons. <i>In vitro</i> tests indicated the normal stability of the resulting C7 variants expressed at physiological levels, while <i>in vivo</i> analyses of regenerated skin grafted onto immunodeficient mice using E73 or E105 RDEB edited cells demonstrated the proper deposition of C7 at the basement membrane zone, thereby restoring normal dermo-epidermal adherence. This study enhances the broader potential of the exon deletion approach in the treatment of RDEB.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1211-1221"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144158326","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":"Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection.","authors":"Sergi Verdés, Xavier Navarro, Assumpció Bosch","doi":"10.1177/10430342251372898","DOIUrl":"10.1177/10430342251372898","url":null,"abstract":"<p><p>Gene therapy is emerging as a transformative approach for treating amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disease. While gene replacement has shown a groundbreaking success in spinal muscular atrophy, the complexity of ALS-due to frequent gain-of-function mutations and a heterogeneous etiology-presents significant challenges. Importantly, approximately 90% of ALS cases are sporadic, with unknown genetic mutation, further complicating patient stratification and therapeutic targeting. As a result, gene therapy strategies must often address multiple pathological mechanisms simultaneously. So far, current gene therapy strategies aim to either suppress toxic gene expression or promote neuroprotection, predominantly via viral-mediated delivery systems. This review will provide an overview of emerging preclinical and clinical gene therapy approaches for ALS, focusing on two main strategies: gene silencing and neuroprotection. Gene silencing techniques, including antisense oligonucleotides (ASOs), viral-mediated RNA interference, and gene editing, have demonstrated efficacy in reducing mutant gene expression, particularly in SOD1 and C9orf72 models, although clinical translation has so far yielded limited success. The recent Food and Drug Administration's approval of the ASO therapy Qalsody for SOD1-ALS underscores the clinical potential of these approaches. Neuroprotective strategies aim to enhance motor neuron survival through delivery of trophic factors, often targeting both central and peripheral tissues to harness retrograde transport mechanisms. We will discuss the advantages and limitations of various delivery vectors, targeting specificity, timing of intervention, and translational challenges, alongside current clinical trial data. This review aims to synthesize how these approaches may converge to address the multifaceted nature of ALS and guide the development of next-generation therapeutics.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1173-1198"},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992291","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}