Gene Therapy最新文献_第4页

Early life safety profiling of gene therapy for spinal muscular atrophy. 脊髓性肌萎缩症基因治疗的早期生命安全性分析。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-01 DOI: 10.1038/s41434-025-00529-6

Rebecca G Spellman, Leillani L Ha, Salomé Da Silva Duarte Lepez, Elizabeth A Arruda, Emma Rodrigues, Kathryn J Swoboda, Christiano R R Alves

{"title":"Early life safety profiling of gene therapy for spinal muscular atrophy.","authors":"Rebecca G Spellman, Leillani L Ha, Salomé Da Silva Duarte Lepez, Elizabeth A Arruda, Emma Rodrigues, Kathryn J Swoboda, Christiano R R Alves","doi":"10.1038/s41434-025-00529-6","DOIUrl":"https://doi.org/10.1038/s41434-025-00529-6","url":null,"abstract":"<p><p>The present study examines the safety profile of intravenous onasemnogene abeparvovec gene therapy in a real-world setting, both alone or in combination with intrathecal antisense oligonucleotide nusinersen therapy in two cohorts of patients with spinal muscular atrophy (SMA). The first cohort included eight presymptomatic infants treated solely with onasemnogene abeparvovec, while the second cohort comprised six symptomatic infants receiving onasemnogene abeparvovec and nusinersen co-therapy. All patients received the corticosteroid prednisolone coincident with gene therapy. Circulating alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were measured to determine potential hepatoxicity, the primary focus of this study. Elevated ALT and AST levels were observed in one pre-symptomatic and three symptomatic patients post-treatment. However, all values returned to normal levels within 3 months of onasemnogene abeparvovec injection. Nusinersen treatment received previously or coincident with gene therapy did not impact the transient elevation of liver transaminases. This study highlights the importance of early intervention with molecular treatments for SMA and indicates that prior or coincident treatment with nusinersen is unlikely to impact safety of onasemnogene apoparvovec and could theoretically improve clinical outcomes in symptomatic infants or in those with gene therapy delayed beyond the immediate neonatal period.</p>","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763695","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

Optimization of adeno-associated viral (AAV) gene therapies vectors for balancing efficacy, longevity and safety for clinical application 腺相关病毒（AAV）基因治疗载体的优化，以平衡临床应用的疗效、寿命和安全性。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-03-26 DOI: 10.1038/s41434-025-00524-x

Neel Mehta, Rénald Gilbert, Parminder S. Chahal, Maria J. Moreno, Nasha Nassoury, Nathalie Coulombe, Richard Gingras, Alaka Mullick, Simon Drouin, Marc Sasseville, Jyoti Latawa, Krishnaraj Tiwari, Wendy Lin, Emily M. Harvey, Fudan Miao, Colin J. D. Ross, Michael R. Hayden

{"title":"Optimization of adeno-associated viral (AAV) gene therapies vectors for balancing efficacy, longevity and safety for clinical application","authors":"Neel Mehta, Rénald Gilbert, Parminder S. Chahal, Maria J. Moreno, Nasha Nassoury, Nathalie Coulombe, Richard Gingras, Alaka Mullick, Simon Drouin, Marc Sasseville, Jyoti Latawa, Krishnaraj Tiwari, Wendy Lin, Emily M. Harvey, Fudan Miao, Colin J. D. Ross, Michael R. Hayden","doi":"10.1038/s41434-025-00524-x","DOIUrl":"10.1038/s41434-025-00524-x","url":null,"abstract":"Adeno-associated viral (AAV) vectors are an ideal platform for gene therapy due to their ability to deliver therapeutic cargos safely and effectively across various target organs. Their low immunogenicity contributes to long-lasting therapeutic effects. However, recent insights highlight the significance of CpG content within AAV vectors, where unmethylated CpG dinucleotides can trigger a TLR9-mediated immune response, leading to the rapid elimination of transduced cells. Clinical evidence indicates an inverse relationship between CpG content and therapeutic success, with lower CpG counts correlating with sustained transgene expression. Here, we sought to optimize a novel, CpG-rich AAV8 vector, referred to as pVR59, designed for treating lipoprotein lipase deficiency (LPLD). We strategically reduced CpG levels in pVR59, resulting in the development of pNC182, a CpG-depleted vector that maintains therapeutic efficacy. A single intramuscular injection of pNC182 demonstrated comparable effectiveness to pVR59 in normalizing lipemia and hypertriglyceridemia in LPLD mouse models, with a 38% reduction in total CpG count. These findings support the clinical application of pNC182 as a safe, long-lasting AAV gene therapy for LPLD and provide a framework for future AAV vector designs aimed at maximizing therapeutic efficacy while minimizing immunogenic responses in human settings.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 3","pages":"197-210"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718538","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

CRISPR targeting of SNPs associated with age-related macular degeneration in ARPE-19 cells: a potential model for manipulating the complement system CRISPR靶向ARPE-19细胞中与年龄相关性黄斑变性相关的snp：操纵补体系统的潜在模型

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-03-18 DOI: 10.1038/s41434-025-00522-z

Ahmed Salman, Won Kyung Song, Tina Storm, Michelle E. McClements, Robert E. MacLaren

{"title":"CRISPR targeting of SNPs associated with age-related macular degeneration in ARPE-19 cells: a potential model for manipulating the complement system","authors":"Ahmed Salman, Won Kyung Song, Tina Storm, Michelle E. McClements, Robert E. MacLaren","doi":"10.1038/s41434-025-00522-z","DOIUrl":"10.1038/s41434-025-00522-z","url":null,"abstract":"Age-related Macular degeneration (AMD) is a major cause of vision loss and is linked to several predisposing single nucleotide polymorphisms (SNPs). CRISPR-mediated genome editing offers the potential to target negatively associated SNPs in an allele-specific manner, necessitating the need for a relevant cell model. The ARPE-19 cell line, with its stable monolayer growth and retinal pigment epithelium (RPE) characteristics, serves as an ideal model for AMD studies. Chronic inflammation and complement system dysregulation are implicated in AMD pathogenesis. Most genetic variations associated with AMD are in complement genes, suggesting their regulatory role. In this study, we conducted targeted PCRs to identify AMD-related SNPs in ARPE-19 cells and used CRISPR constructs to assess allele-specific activity. Guide RNA sequences were cloned into an EF-1-driven SpCas9 vector and packaged into lentivirus. Targeting efficiencies were evaluated with TIDE analysis, and allele-specificity was measured with NGS analysis 30 days post-transduction. Our results showed varying targeting efficiencies depending on guide RNA efficacy. For example, TIDE analysis of CFH SNPs rs1061170 and rs1410996 revealed efficiencies of 35.5% and 33.8%, respectively. CFB SNP rs4541862 showed efficiencies from 3% to 36.7%, and rs641153 ranged from 3.4% to 23.8%. Additionally, allele-specific targeting of AMD-related SNPs rs1061170, rs1410996, rs4541862, and rs641153 ranged from 48% to 52% in heterozygous differentiated ARPE-19 cells. These findings demonstrate the potential to manipulate the complement system in an AMD model by targeting disease-associated SNPs in an allele-specific manner, offering a promising therapeutic approach.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"132-141"},"PeriodicalIF":4.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-025-00522-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AAV vector engineering for human aorta transduction: becoming a smooth operator AAV载体工程用于人主动脉转导：成为一个平滑算子。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-03-17 DOI: 10.1038/s41434-025-00526-9

Kleopatra Rapti, Dirk Grimm

引用次数: 0

Improved induction of ribozyme-controlled AAV transgene via peptide-conjugated morpholino oligos 利用肽偶联寡核苷酸改进诱导核酶控制的AAV转基因。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-26 DOI: 10.1038/s41434-025-00520-1

Tianyi Cheng, Baohui Chen, Wei Zou

引用次数: 0

A capless hairpin-protected mRNA vaccine encoding the full-length Influenza A hemagglutinin protects mice against a lethal Influenza A infection 一种编码全长甲型流感血凝素的无帽发夹保护mRNA疫苗保护小鼠免受致命甲型流感感染。

IF 4.5 3区医学

Gene Therapy Pub Date : 2025-02-23 DOI: 10.1038/s41434-025-00521-0

Victor Solodushko, Jin H. Kim, Brian Fouty

{"title":"A capless hairpin-protected mRNA vaccine encoding the full-length Influenza A hemagglutinin protects mice against a lethal Influenza A infection","authors":"Victor Solodushko, Jin H. Kim, Brian Fouty","doi":"10.1038/s41434-025-00521-0","DOIUrl":"10.1038/s41434-025-00521-0","url":null,"abstract":"The success of mRNA vaccines in controlling the COVID 19 pandemic has confirmed the efficacy of synthetically synthesized mRNA in humans and has also provided a blueprint on how to design them in terms of molecular structure and cost. We describe a mRNA vector that, unlike linear mRNAs used in current vaccines/therapeutics, does not require a 5′ cap to function. The described mRNA vector initiates translation from an internal ribosomal entry site (IRES) and contains specially designed self-folding secondary structures (hairpins) to protect the 5′ end against degradation, dramatically improving its stability. The produced mRNA did not require any additional modifications for functionality. The 5′ hairpins completely inhibited cap-dependent translation, and all vectors containing them required an IRES to express protein. When this capless mRNA vector was constructed to express the full-length Influenza A membrane protein hemagglutinin (HA), complexed with pre-formed lipid-based nanoparticles, and then injected into mice as a vaccine, it generated high titers of anti-HA antibodies and protected mice against a lethal dose of Influenza A.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 4","pages":"349-358"},"PeriodicalIF":4.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice 一种肽偶联物可以使morpholino诱导剂全身注射，并在小鼠中更持久地诱导T3H38核酶控制的AAV转基因。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-12 DOI: 10.1038/s41434-025-00519-8

Xiaojuan Tang, Haimin Wang, Yandong Yin, Guocai Zhong

{"title":"A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice","authors":"Xiaojuan Tang, Haimin Wang, Yandong Yin, Guocai Zhong","doi":"10.1038/s41434-025-00519-8","DOIUrl":"10.1038/s41434-025-00519-8","url":null,"abstract":"Genetic switches that allow for precise control over transgene expression timing or levels may improve the safety and expand the use of adeno-associated viral (AAV) vector-based gene therapy technologies. We previously engineered an efficient RNA switch system that comprises a novel self-cleaving ribozyme (T3H38) and an octaguanidine dendrimer-conjugated morpholino oligonucleotide (v-M8) complementary to the ribozyme. This switch system can be used to efficiently regulate AAV-delivered transgenes with an up to 200-fold regulatory range in mice. However, this switch system has a relatively short induction half-life and only works well when v-M8 was locally but not systemically administered, representing two key limitations of the system. To address these issues, here, we tested replacing the octa-guanidine dendrimer in the v-M8 morpholino oligo with a cell-penetrating peptide (CPP). Two CPP-conjugated morpholino oligos (B-M8 and B-MSP-M8) were synthesized and compared with v-M8 for the induction of T3H38-regulated AAV-luciferase in mice. One of the CPP-conjugated oligos (B-MSP-M8) not only showed significantly improved induction half-life over that of v-M8, but also enabled efficient induction of AAV transgene expression when the oligo was systemically administered. This study improves in vivo performance and broadens the utility of the T3H38 ribozyme-based RNA switch system in gene therapy applications.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"32 2","pages":"163-171"},"PeriodicalIF":4.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407108","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

Focused ultrasound widely broadens AAV-delivered Cas9 distribution and activity 聚焦超声广泛拓宽了aav递送的Cas9分布和活性。

IF 4.5 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":"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":"32 3","pages":"237-245"},"PeriodicalIF":4.5,"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

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 4.5 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":"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":"32 3","pages":"287-298"},"PeriodicalIF":4.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106068/pdf/","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":"OA","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 4.5 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":"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":"32 3","pages":"211-222"},"PeriodicalIF":4.5,"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