Human gene therapy最新文献

Preclinical Assessment of Antibody Responses to Adeno-Associated Virus (AAV) Vector-Based Capsids of AAV2, AAV5, AAV8, or AAV9 in Laboratory Cynomolgus Macaques (Macaca fascicularis) of Asian or Mauritian Origin. 亚洲或毛里求斯实验室食蟹猴（Macaca fascularis）对腺相关病毒（AAV）载体衣壳AAV2、AAV5、AAV8或AAV9抗体反应的临床前评估

IF 4 3区医学

Human gene therapy Pub Date : 2025-09-12 DOI: 10.1177/10430342251376043

Betina Pajaziti, Ulf Michgehl, Dragica Blazevic, Franziska Fimm-Todt, Alexandra Duetting, Birgit Korbmacher, Stephanie Grote-Wessels, Stefan Michelfelder, Lars Mecklenburg

{"title":"Preclinical Assessment of Antibody Responses to Adeno-Associated Virus (AAV) Vector-Based Capsids of AAV2, AAV5, AAV8, or AAV9 in Laboratory Cynomolgus Macaques (Macaca fascicularis) 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":"https://doi.org/10.1177/10430342251376043","url":null,"abstract":"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 (Macaca fascicularis) 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 in vitro neutralizing antibody (NAB) assay to detect NAB titers or an in vitro 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 in vitro 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 in vitro TAB assay. Notably, co-prevalences of antibody responses against AAV2, AAV8, and AAV9 serotypes resulted in 39.8% seropositivity (in vitro NAB assay) in NHPs of Asian and in about 32.6% (in vitro TAB assay) of Mauritian origin.","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}

引用次数: 0

Targeting Amyotrophic Lateral Sclerosis with Gene Therapy: From Silencing Genes to Enhancing Neuroprotection. 针对肌萎缩侧索硬化症的基因治疗：从沉默基因到增强神经保护。

IF 4 3区医学

Human gene therapy Pub Date : 2025-09-04 DOI: 10.1177/10430342251372898

Sergi Verdés, Xavier Navarro, Assumpció Bosch

{"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":"https://doi.org/10.1177/10430342251372898","url":null,"abstract":"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.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-04","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}

引用次数: 0

Advancements in Nonviral Gene Editing Strategies for Rare Diseases. 罕见病非病毒基因编辑策略研究进展

IF 4 3区医学

Human gene therapy Pub Date : 2025-09-01 DOI: 10.1177/10430342251372056

Jimena Pérez-Maroto, Laura Sepp-Lorenzino, Diego Castaño-Esteban, Daniela Palacios, Begoña Sot

{"title":"Advancements in Nonviral Gene Editing Strategies for Rare Diseases.","authors":"Jimena Pérez-Maroto, Laura Sepp-Lorenzino, Diego Castaño-Esteban, Daniela Palacios, Begoña Sot","doi":"10.1177/10430342251372056","DOIUrl":"https://doi.org/10.1177/10430342251372056","url":null,"abstract":"Rare diseases are serious and often chronic conditions that affect a small number of individuals. However, with over 7,000 rare diseases identified, their cumulative global numbers and impact are substantial. A considerable proportion of these conditions is caused by genetic abnormalities. Among these, monogenic disorders are of particular relevance, as they are caused by mutations in specific genes. The development of gene therapy, and more specifically, gene editing, offers innovative approaches to treat these rare diseases. A significant challenge associated with the implementation of such strategies concerns the delivery of gene editing tools. Nonviral vectors based on nanomaterials have demonstrated considerable potential as promising alternatives to viral vectors, thereby overcoming their disadvantages. The biocompatibility and tunability of nanoparticles, along with their potential capacity to target diverse tissues, positions them as a promising therapeutic approach for the treatment of a wide range of organ-specific rare diseases. Here, we review current progress in the development and evaluation of novel nanomedicine strategies for gene editing in rare diseases, highlighting new gene editing approaches, delivery systems, and potential targets.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952013","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

Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case. 慢病毒载体和造血干细胞基因治疗的风险和效益评估：Skysona病例。

IF 4 3区医学

Human gene therapy Pub Date : 2025-09-01 DOI: 10.1177/10430342251372474

Pilar Puig-Serra, Ana Hinckley-Boned, María Tristán-Manzano, Paula Rio, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Francisco Martín

{"title":"Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case.","authors":"Pilar Puig-Serra, Ana Hinckley-Boned, María Tristán-Manzano, Paula Rio, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Francisco Martín","doi":"10.1177/10430342251372474","DOIUrl":"https://doi.org/10.1177/10430342251372474","url":null,"abstract":"Seven cases of hematological malignancy reported in recipients of Skysona™ (elivaldogene autotemcel) have reignited long-standing concerns about insertional mutagenesis in lentiviral vector (LV)-based gene therapy. Here, we dissect the molecular and clinical evidence underlying these events, place them in the broader context of over 300 patients treated with LV-modified hematopoietic stem and progenitor cells (HSPCs), and review the real-world safety record of LV-engineered chimeric antigen receptor T cells. We show that cancers associated with Skysona are mechanistically linked to the use of a potent viral MNDU3 promoter probably combined with intensive conditioning and growth-factor support, whereas LV products employing weak or physiological promoters continue to display an excellent safety profile. With event rates <0.6/100 patient-years, lower than those after autologous HSCT, the therapeutic index of approved LV-HSPC advanced therapy medicinal products remains favorable. Ongoing optimization of vector design, conditioning, and long-term surveillance, together with emerging genome-editing platforms, is expected to further mitigate residual risk.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952055","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

Genetic Engineering in CAR T Cells for Solid Tumors: Current State, Barriers and Future Developments. CAR - T细胞用于实体肿瘤的基因工程：现状、障碍和未来发展。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-29 DOI: 10.1177/10430342251372041

Rodrigo A Redondo-Frutos, Pedro Justicia-Lirio, Carmen Barbero-Jimenez, Maider Garnica, Lucia Trudu, Paula Rodriguez-Marquez, Juan J Lasarte, Felipe Prosper, Juan R Rodriguez-Madoz

{"title":"Genetic Engineering in CAR T Cells for Solid Tumors: Current State, Barriers and Future Developments.","authors":"Rodrigo A Redondo-Frutos, Pedro Justicia-Lirio, Carmen Barbero-Jimenez, Maider Garnica, Lucia Trudu, Paula Rodriguez-Marquez, Juan J Lasarte, Felipe Prosper, Juan R Rodriguez-Madoz","doi":"10.1177/10430342251372041","DOIUrl":"https://doi.org/10.1177/10430342251372041","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment for hematological malignancies, yet translating this success to solid tumors remains challenging. Major obstacles include antigen heterogeneity, on-target off-tumor toxicity, limited infiltration and persistence, and the immunosuppressive tumor microenvironment (TME). The present review discusses recent engineering strategies designed to overcome these barriers. Innovations such as affinity-tuned and logic-gated CARs improve specificity and safety, while multi-antigen targeting helps address tumor heterogeneity by avoiding antigen escape. Gene-editing approaches enhance CAR T cell fitness by promoting memory phenotypes, metabolic resilience, and resistance to inhibitory signals imposed by the immunosuppressive TME. Additional modifications improve trafficking, enable extracellular matrix degradation, and reprogram CAR T cells to withstand the hostile conditions of the TME. Together, these advances reflect a growing shift toward rational CAR design and synthetic immunology, with the goal of achieving durable and safe responses in solid tumors. Early clinical trials show promise, and continued translational efforts will be key to unlocking the full therapeutic potential of CAR T cells in this setting.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"0"},"PeriodicalIF":4.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952018","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

Hospital Exemption for Advanced Therapy Medicinal Products in Spain. 西班牙高级治疗药品的医院豁免。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-22 DOI: 10.1177/10430342251372050

Marcos Timón, Sol Ruiz

引用次数: 0

The Coming of Age of Gene Therapy for the Treatment of Human Diseases: A Regulatory Perspective. 基因治疗人类疾病时代的到来：一个调控的视角。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-22 DOI: 10.1177/10430342251372047

Laura Rodríguez, Pablo de Felipe, Raquel Martín, Jorge Martínez, David Ordóñez, Susana Rojo, Juan Fernando Martínez, Esther Rincón, Teresa Cejalvo, Irene Izquierdo, Inmaculada Montanuy, Marcos Timón

{"title":"The Coming of Age of Gene Therapy for the Treatment of Human Diseases: A Regulatory Perspective.","authors":"Laura Rodríguez, Pablo de Felipe, Raquel Martín, Jorge Martínez, David Ordóñez, Susana Rojo, Juan Fernando Martínez, Esther Rincón, Teresa Cejalvo, Irene Izquierdo, Inmaculada Montanuy, Marcos Timón","doi":"10.1177/10430342251372047","DOIUrl":"https://doi.org/10.1177/10430342251372047","url":null,"abstract":"After many years of promising clinical results splashed with some serious adverse events, gene therapy has finally reached maturity, as demonstrated by the increasing number of medicinal products approved for commercialization by regulatory authorities. The approved products tackle monogenetic inherited diseases as well as cancer, include both in vivo and ex vivo approaches, and comprise mostly gene additions but also a genome-edited product, demonstrating proof of concept for most gene therapy modalities. Uncertainties still remain, especially on their long-term safety and efficacy, which can only be solved with time. These successes should not lead to self-complacency but rather stimulate the development of necessary improvements concerning manufacturing or the safety and efficacy profile. Here, we review the different categories of gene therapy medicinal products and highlight potential areas for improvement. Products approved for commercialization are taken as the basis for the discussion, since information on their assessment is publicly available. New products and manufacturing approaches under development are also reviewed, with an emphasis on the regulatory challenges expected for some of them.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952046","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

Sarepta Pauses, then Resumes, Shipments of DMD Gene Therapy. Sarepta暂停，然后恢复DMD基因疗法的运输。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-22 DOI: 10.1177/10430342251372903

Alex Philippidis

引用次数: 0

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes microRNA-31-5p Repress Pulmonary Fibrosis via IGFBP7. 骨髓间充质干细胞来源的外泌体microRNA-31-5p通过IGFBP7抑制肺纤维化。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-14 DOI: 10.1177/10430342251366273

Lingrui Zhang, Ke Qiu, Chenchen Zhang, Jiaqing Wu

{"title":"Bone Marrow Mesenchymal Stem Cell-Derived Exosomes microRNA-31-5p Repress Pulmonary Fibrosis via IGFBP7.","authors":"Lingrui Zhang, Ke Qiu, Chenchen Zhang, Jiaqing Wu","doi":"10.1177/10430342251366273","DOIUrl":"10.1177/10430342251366273","url":null,"abstract":"Bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) with their molecular cargo have therapeutic potential for pulmonary fibrosis (PF). This research was performed to uncover how microRNA-31-5p (miR-31-5p), carried by BMSCs-Exos, affects PF via modulating IGFBP7. C57BL/6 mice were treated with bleomycin (BLM) to induce PF. Pulmonary function was tested, and fibrotic changes in the mouse lung tissues were examined. Levels of fibrosis-related inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, were tested. Mouse BMSCs were isolated and identified, and BMSCs-Exos were obtained by ultracentrifugation. Exosome morphology was observed by transmission electron microscopy, the surface markers were measured, and the expression levels of BMSCs-Exo marker proteins were assessed. The targeting relation between miR-31-5p and IGFBP7 was assessed, and the expression of both was tested. After modeling, mice exhibited decreased functional residual capacity, lung compliance, inspiratory capacity, vital capacity, total lung capacity, and forced vital capacity. After 14 days of BLM induction, thickening of the main tracheal wall, fibroblast accumulation, immune cell infiltration in lung interstitium, and increased collagen deposition were observed. Elevated levels of TNF-α, IL-1β, and IL-6 were also noted. BMSCs-Exos attenuated BLM-induced PF, and BMSCs-Exo-derived miR-31-5p ameliorated PF in mice. miR-31-5p was shown to target IGFBP7, diminishing both transcript and protein levels. IGFBP7 overexpression reversed the ameliorative impact of miR-31-5p on PF in mice. BMSCs-Exos ameliorate PF development by delivering miR-31-5p to repress IGFBP7.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872990","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

Medicinal Products Based on Adeno-Associated Viral Vectors: A Regulatory Perspective on the Potential Risk of Insertion-Mediated Tumorigenesis. 基于腺相关病毒载体的医药产品：对插入介导的肿瘤发生潜在风险的调控观点。

IF 4 3区医学

Human gene therapy Pub Date : 2025-08-11 DOI: 10.1177/10430342251366314

Egbert Flory, Martin Walter, Violaine Closson-Carella, Patrick Celis, Martina Schuessler-Lenz, Ilona Reischl

{"title":"Medicinal Products Based on Adeno-Associated Viral Vectors: A Regulatory Perspective on the Potential Risk of Insertion-Mediated Tumorigenesis.","authors":"Egbert Flory, Martin Walter, Violaine Closson-Carella, Patrick Celis, Martina Schuessler-Lenz, Ilona Reischl","doi":"10.1177/10430342251366314","DOIUrl":"https://doi.org/10.1177/10430342251366314","url":null,"abstract":"The first marketed gene therapy medicinal products based on adeno-associated virus (AAV-GTMP) show promise for the treatment of various diseases, including rare diseases with unmet medical needs. AAV is traditionally considered nonpathogenic to humans, is incapable of self-replication, and, after introduction into various cell types, remains primarily episomal. Several reports have examined the risks of AAV-GTMP, including the risks associated with unintended integration events of elements from the recombinant (r) AAV vector into the host genome. Such events can be one of the steps in the multistep process of tumor formation. To date, rAAV-gene therapy (GT) vectors have not been shown to induce tumors in humans or non-rodent species, and the potential for rAAV-mediated carcinogenicity in humans is still considered theoretical. Nevertheless, a critical review of publicly available scientific data on rAAV-related integration events and a contextualization of the numbers of AAV-GT vector DNA integrations with the absolute burdens of environmental, lifestyle and background tumorigenic genotoxicities is warranted. From a regulatory perspective, it is advisable to implement a long-term safety follow-up for patients who have undergone treatment with high doses of AAV-GT, in accordance with the risk-based approach that has been established for advanced therapy medicinal products.","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821290","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