Gene Therapy最新文献

Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-01 DOI: 10.1038/s41434-025-00517-w

Emrah Gumusgoz, Sahba Kasiri, Ibrahim Youssef, Mayank Verma, Rajiv Chopra, Daniel Villarreal Acha, Jun Wu, Ummay Marriam, Esther Alao, Xin Chen, Dikran R Guisso, Steven J Gray, Bhavya R Shah, Berge A Minassian

{"title":"Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity.","authors":"Emrah Gumusgoz, Sahba Kasiri, Ibrahim Youssef, Mayank Verma, Rajiv Chopra, Daniel Villarreal Acha, Jun Wu, Ummay Marriam, Esther Alao, Xin Chen, Dikran R Guisso, Steven J Gray, Bhavya R Shah, Berge A Minassian","doi":"10.1038/s41434-025-00517-w","DOIUrl":"https://doi.org/10.1038/s41434-025-00517-w","url":null,"abstract":"Because children have little temporal exposure to environment and aging, most pediatric neurological diseases are inherent, i.e. genetic. Since postnatal neurons and astrocytes are mostly non-replicating, gene therapy and genome editing present enormous promise in child neurology. Unlike in other organs, which are highly permissive to adeno-associated viruses (AAV), the mature blood-brain barrier (BBB) greatly limits circulating AAV distribution to the brain. Intrathecal administration improves distribution but to no more than 20% of brain cells. Focused ultrasound (FUS) opens the BBB transiently and safely. In the present work we opened the hippocampal BBB and delivered a Cas9 gene via AAV9 intrathecally. This allowed brain first-pass, and subsequent vascular circulation and re-entry through the opened BBB. The mouse model used was of Lafora disease, a neuroinflammatory disease due to accumulations of misshapen overlong-branched glycogen. Cas9 was targeted to the gene of the glycogen branch-elongating enzyme glycogen synthase. We show that FUS dramatically (2000-fold) improved hippocampal Cas9 distribution and greatly reduced the pathogenic glycogen accumulations and hippocampal inflammation. FUS is in regular clinical use for other indications. Our work shows that it has the potential to vastly broaden gene delivery or editing along with clearance of corresponding pathologic basis of brain disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074449","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

Correction: The disparate burden of infectious diseases 更正：传染病造成的不同负担。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-26 DOI: 10.1038/s41434-025-00516-x

Kristie Bloom

引用次数: 0

Incomplete elimination of viral genomes is associated with chronic inflammation in nonhuman primate livers after AAV-mediated gene transfer. 在aav介导的基因转移后，病毒基因组的不完全消除与非人灵长类动物肝脏的慢性炎症有关。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-21 DOI: 10.1038/s41434-025-00514-z

Virginie Pichard, Mickaël Guilbaud, Marie Devaux, Nicolas Jaulin, Malo Journou, Magalie Cospolite, Alexandra Garcia, Nicolas Ferry, Sophie Michalak-Provost, Gwladys Gernoux, Oumeya Adjali

{"title":"Incomplete elimination of viral genomes is associated with chronic inflammation in nonhuman primate livers after AAV-mediated gene transfer.","authors":"Virginie Pichard, Mickaël Guilbaud, Marie Devaux, Nicolas Jaulin, Malo Journou, Magalie Cospolite, Alexandra Garcia, Nicolas Ferry, Sophie Michalak-Provost, Gwladys Gernoux, Oumeya Adjali","doi":"10.1038/s41434-025-00514-z","DOIUrl":"https://doi.org/10.1038/s41434-025-00514-z","url":null,"abstract":"The liver is a unique organ where immunity can be biased toward ineffective response notably in the context of viral infections. Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. In the case of recombinant Adeno-Associated-Virus, used for therapeutic gene transfer, conflicting reports describe tolerance induction to different transgene products while other studies have shown conventional cytotoxic CD8+ T cell responses with a rapid loss of transgene expression. We performed a 1 year follow up of 6 non-human primates after all animals received an rAAV8 vector carrying the GFP transgene at doses of 7×1012 vg/kg. We report that despite anti-GFP peripheral cellular response and loss of hepatic transgene expression, we were still able to detect persisting viral genomes in the liver until 1-year post-injection. These viral genomes were associated with liver inflammation, fibrosis and signs of CD8 T cell exhaustion, including high expression of PD-1. Our study shows that AAV8-mediated gene transfer can results to loss of transgene expression in liver and chronic inflammation several months after gene transfer.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004306","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

Co-delivery of IL-1Ra and SOX9 via AAV inhibits inflammation and promotes cartilage repair in surgically induced osteoarthritis animal models. 在手术诱导的骨关节炎动物模型中，通过AAV共同递送IL-1Ra和SOX9可抑制炎症并促进软骨修复。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-20 DOI: 10.1038/s41434-025-00515-y

Kaiyi Zhou, Meng Yuan, Jiabao Sun, Feixu Zhang, Xinting Li, Xiao Xiao, Xia Wu

{"title":"Co-delivery of IL-1Ra and SOX9 via AAV inhibits inflammation and promotes cartilage repair in surgically induced osteoarthritis animal models.","authors":"Kaiyi Zhou, Meng Yuan, Jiabao Sun, Feixu Zhang, Xinting Li, Xiao Xiao, Xia Wu","doi":"10.1038/s41434-025-00515-y","DOIUrl":"https://doi.org/10.1038/s41434-025-00515-y","url":null,"abstract":"Osteoarthritis (OA), a prevalent joint disorder, can lead to disability, with no effective treatment available. Interleukin-1 (IL-1) plays a crucial role in the progression of OA, and its receptor antagonist (IL-1Ra), a natural IL-1 inhibitor, represents a promising therapeutic target by obstructing the IL-1 signaling pathway. This study delivered IL-1Ra via adeno-associated virus (AAV), a gene therapy vector enabling long-term protein expression, to treat knee osteoarthritis (KOA) in animal models. scAAV-oIL-1Ra-I1/2 injected directly into the joint in both MMT/ACLT-induced KOA model rat improved abnormal gait (increasing footprint area and pressure), subchondral bone lesions, and significantly reduced cartilage wear and pathological scores. In the MMT-induced KOA rabbit model, weight-bearing asymmetry (indicating pain) improved after 8 weeks of scAAV-oIL-1Ra-I1/2 administration, and X-ray showed decreased K-L scores (severity grade), reduced cartilage loss, and lower pathology scores compared to untreated animals. Additionally, sex-determining region Y-type high mobility group box 9 (SOX9) was co-delivered with IL-1Ra via AAV in ACLT + MMT-induced KOA rats. The combined treatment significantly alleviated subchondral bone lesions, cartilage destruction, synovial inflammation, and pathological scores, demonstrating superior efficacy compared to either treatment administered alone. Co-delivering IL-1Ra and SOX9 inhibited IL-1 mediated inflammatory signaling, maintained cartilage homeostasis, and promoted its repair in KOA models, suggesting potential for clinical use.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004299","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

Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials. 一种新型IgG降解酶（KJ103）的安全性、有效性和免疫原性：来自两项随机、盲法1期临床试验的结果

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-18 DOI: 10.1038/s41434-025-00512-1

Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R Marshall, Yanxia Yu, Zheng Wang

{"title":"Safety, efficacy, and immunogenicity of a novel IgG degrading enzyme (KJ103): results from two randomised, blinded, phase 1 clinical trials.","authors":"Mengdie Cao, Rohit Katial, Yanjun Liu, Xiaoyu Lu, Qin Gu, Chen Chen, Katie Liu, Zhen Zhu, Mark R Marshall, Yanxia Yu, Zheng Wang","doi":"10.1038/s41434-025-00512-1","DOIUrl":"https://doi.org/10.1038/s41434-025-00512-1","url":null,"abstract":"The approved intravenous adeno-associated virus (AAV) therapies are limited by the widespread prevalence of pre-existing anti-AAV antibodies in the general population, which are known to restrict patients' ability to receive gene therapy and limit transfection efficacy in vivo. To address this challenge, we have developed a novel recombinant human immunoglobulin G degrading enzyme KJ103, characterized by low immunogenicity and clinical value for the elimination of anti-AAV antibodies in gene transfer. Herein, we conducted two randomized, blinded, placebo-controlled, single ascending dose Phase I studies in China and New Zealand, to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of KJ103 in healthy volunteers. The results confirmed that KJ103 rapidly reduced IgG and maintained plasma IgG at low levels for one week. Dose of KJ103 ranging from 0.01 to 0.40 mg/kg had a favorable safety and tolerability profile across diverse ethnic and gender groups. KJ103 demonstrated a lower incidence of pre-existing anti-drug antibodies (ADAs) compared to currently approved human IgG degrading enzyme Imlifidase, with most induced ADAs predominantly reverting to baseline six months after administration. These properties are ideal for the management of immune disorders, rejection responses, and immunotherapies where pre-existing antibodies can reduce efficacy. Furthermore, we tested AAV2 neutralizing antibodies to confirm the potential utility of KJ103 in enhancing gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004311","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

Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy. 基因治疗后靶向蛋白质组学发现脊髓性肌萎缩症的新反应标志物。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-01-10 DOI: 10.1038/s41434-025-00513-0

Devesh C Pant, Sumit Verma

{"title":"Identifying novel response markers for spinal muscular atrophy revealed by targeted proteomics following gene therapy.","authors":"Devesh C Pant, Sumit Verma","doi":"10.1038/s41434-025-00513-0","DOIUrl":"https://doi.org/10.1038/s41434-025-00513-0","url":null,"abstract":"Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964493","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

Correction: RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells. 更正：rapacaspase -9型自杀基因应用于IL-1RAP CAR-T细胞的安全性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-20 DOI: 10.1038/s41434-024-00487-5

Lucie Bouquet, Elodie Bôle-Richard, Walid Warda, Mathieu Neto Da Rocha, Rim Trad, Clémentine Nicod, Rafik Haderbache, Delphine Genin, Christophe Ferrand, Marina Deschamps

引用次数: 0

AAV library screening identifies novel vector for efficient transduction of human aorta. AAV文库筛选为人类主动脉高效转导找到了新的载体。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-18 DOI: 10.1038/s41434-024-00511-8

Lena C Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J Müller

{"title":"AAV library screening identifies novel vector for efficient transduction of human aorta.","authors":"Lena C Schröder, Leonard Hüttermann, Anca Kliesow Remes, Jakob C Voran, Susanne Hille, Wiebke Sommer, Georg Lutter, Gregor Warnecke, Derk Frank, Dennis Schade, Oliver J Müller","doi":"10.1038/s41434-024-00511-8","DOIUrl":"https://doi.org/10.1038/s41434-024-00511-8","url":null,"abstract":"Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding. This approach allowed us to distinguish capsids that only transduce cells based on genomic DNA (gDNA) from those also mediating transgene expression based on transcribed cDNA reads. After three rounds of selection on primary murine VSMCs (mVSMCs), we identified a novel targeting motif (RFTEKPA) that significantly improved transduction and gene expression efficiency over AAV9-wild type (WT) and increased expression in mVSMCs by 70% compared to the previously identified SLRSPPS peptide. Further analysis showed that the novel motif also improved expression in human aortic smooth muscle cells (HAoSMCs) and human aortic tissue ex vivo up to threefold compared to SLRSPPS and approximately 70-fold to AAV9-WT. This high cross-species transduction efficiency makes the novel capsid motif a potential candidate for future clinical application in vascular diseases.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853989","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

Intracisternal vs intraventricular injection of AAV1 result in comparable, widespread transduction of the dog brain. 胸腔内注射 AAV1 与脑室内注射 AAV1 在狗脑中产生的广泛转导效果相当。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-09 DOI: 10.1038/s41434-024-00510-9

Jacqueline E Hunter, Charles H Vite, Caitlyn M Molony, Patricia A O'Donnell, John H Wolfe

{"title":"Intracisternal vs intraventricular injection of AAV1 result in comparable, widespread transduction of the dog brain.","authors":"Jacqueline E Hunter, Charles H Vite, Caitlyn M Molony, Patricia A O'Donnell, John H Wolfe","doi":"10.1038/s41434-024-00510-9","DOIUrl":"https://doi.org/10.1038/s41434-024-00510-9","url":null,"abstract":"Widespread distribution of transduced brain cells following delivery of AAV vectors into the cerebrospinal fluid (CSF) of the cisterna magna (CM) has been demonstrated in large animal brains. In humans, intraventricular injection is preferred to intracisternal injection for CSF delivery due to the risk of brain stem injury. One study in the dog reported adverse reactions to AAV vectors expressing GFP injected into the lateral ventricle but not when injected into the CM. In contrast, AAV expressing mammalian genes in diseased animals have not triggered adverse responses since many genetic diseases also have compromised immune systems. Differences in circulation of CSF from each site could potentially affect vector spread within the brain, but a direct comparison has not been made using both a mammalian gene and immunologically normal animals. In this study we evaluated the dopamine-2-receptor (D2R) variant D2R80A, which is inactivated for intracellular signaling and has been used as a reporter gene in large animal brains. No adverse reactions to the D2R80A gene were observed from either injection route in normal dogs and both routes resulted in comparable distribution of D2R80A within the brain.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800312","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

Unlocking patient access to gene therapy: five key practices. 开启患者获得基因治疗的途径：五个关键实践。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-12-06 DOI: 10.1038/s41434-024-00509-2

Tay Salimullah, Burcu Kazazoglu Taylor, Madeleine Zerbato

引用次数: 0