Gene Therapy最新文献

Is dystrophin immunogenicity a barrier to advancing gene therapy for Duchenne muscular dystrophy? 肌营养不良蛋白免疫原性是推进杜氏肌营养不良基因治疗的障碍吗？

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-03 DOI: 10.1038/s41434-025-00531-y

Dariusz C Górecki, Pawel Kalinski, Joanna Pomeroy

{"title":"Is dystrophin immunogenicity a barrier to advancing gene therapy for Duchenne muscular dystrophy?","authors":"Dariusz C Górecki, Pawel Kalinski, Joanna Pomeroy","doi":"10.1038/s41434-025-00531-y","DOIUrl":"10.1038/s41434-025-00531-y","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to severe disability and premature death in young men. As DMD is caused by the absence of dystrophin, therapeutic development has focused on strategies to restore dystrophin expression. These include readthrough of premature stop codons, exon skipping to restore the reading frame, and gene therapy. The first two methods are mutation-specific, benefiting only subsets of patients, whereas gene therapy could treat all individuals with DMD. Immunogenicity of dystrophin may challenge these efforts. The immune system can recognize dystrophin as a neo-antigen, just as it can recognize newly arising antigens present on mutated cells. An in-depth evaluation of anti-dystrophin immune response as a factor affecting the treatment effectiveness is needed. Key questions include the underlying mechanisms of immunity induction by antigenic epitopes of the re-expressed dystrophin, the impact of such responses on the therapeutic efficacy, and the role of patient-specific risk factors, such as preimmunization due to revertant fibres, chronic muscle inflammation, pre-existing T lymphocytes reactive to dystrophin, which avoided deletion in dystrophic thymus, or antigen cross-reactivity. Patients' immune status assessment before treatment may help mitigating anti-dystrophin responses. Exploring potential therapeutic strategies to enhance treatment outcomes is also essential: Since DMD can be diagnosed at birth, early dystrophin re-expression could prevent damage and also potentially induce neonatal tolerance. In older patients, carefully managed immunosuppression and tolerogenic protocols could pave the way for more successful dystrophin replacement therapies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779746","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

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":"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.","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

Organoids - the future of pre-clinical development of AAV gene therapy for CNS disorders. 类器官- AAV基因治疗中枢神经系统疾病临床前发展的未来。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-03-27 DOI: 10.1038/s41434-025-00527-8

Vivienne M Kaiser, Anai Gonzalez-Cordero

{"title":"Organoids - the future of pre-clinical development of AAV gene therapy for CNS disorders.","authors":"Vivienne M Kaiser, Anai Gonzalez-Cordero","doi":"10.1038/s41434-025-00527-8","DOIUrl":"10.1038/s41434-025-00527-8","url":null,"abstract":"Advancements in our understanding of genetic disease and adeno-associated virus has prompted great excitement into the field of AAV-mediated gene therapy, particularly for genetic diseases of the central nervous system, including retinal disorders. Despite significant progress, exemplified by the approval of therapies such as Luxturna® and Zolgensma®, a substantial number of therapies remain in pre-clinical or early clinical stages, with many failing to advance to later phases. Whilst the use of animal models to test safety and delivery route efficacy of AAV treatments is imperative, differences in tissue structure and physiology between humans and animal models has restricted precise disease modelling and gene therapy development for many CNS disorders. Alongside the FDA push for non-animal alternative models, researchers are increasingly turning to human-based models, including stem cell-derived organoids, which can offer a more accurate representation of human cellular microenvironments and niches. As such, this review explores the advantages and limitations of brain and retinal organoids as pre-clinical models of disease, with a primary focus on their utility in identifying novel AAV capsids, cell-specific promoters, and their role in recent pre-clinical AAV gene therapy studies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729715","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 4.6 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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.6,"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-based gene replacement therapy prevents and halts manifestation of abnormal neurological phenotypes in a novel mouse model of PMM2-CDG. 在一种新型PMM2-CDG小鼠模型中，基于aav的基因替代疗法可以预防和停止异常神经表型的表现。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-03-17 DOI: 10.1038/s41434-025-00525-w

Mian-Ling Zhong, Kent Lai

{"title":"AAV-based gene replacement therapy prevents and halts manifestation of abnormal neurological phenotypes in a novel mouse model of PMM2-CDG.","authors":"Mian-Ling Zhong, Kent Lai","doi":"10.1038/s41434-025-00525-w","DOIUrl":"https://doi.org/10.1038/s41434-025-00525-w","url":null,"abstract":"Inherited Phosphomannomutase 2 (PMM2) deficiency, also known as PMM2-CDG, is the most prevalent N-linked congenital disorder of glycosylation (CDG), occurring in approximately 1 in 20,000 individuals in certain populations. Patients exhibit a spectrum of symptoms, with neurological involvement being a prominent feature, often manifesting as the initial clinical sign, and can range from isolated neurological deficits to severe multi-organ dysfunction. Given the absence of curative treatments and a high mortality rate before the age of two, alongside considerable lifelong morbidity, there is an urgent need for innovative therapeutic approaches. To address this unmet need, we developed a tamoxifen-inducible Pmm2 knockout (KO) mouse model with widespread tissue deficiency of Pmm2 expression. Characterization of the mouse model to-date revealed distinct neurological phenotypes relevant to PMM2-CDG, as assessed by the Composite Phenotype Scoring System and Open Field Test. Notably, PMM2 augmentation through AAV9-PMM2 gene replacement therapy prevented and halted the disease-relevant neurological phenotypes induced by Pmm2 KO in the animals. These findings underscored the promise of AAV9-PMM2 gene replacement in managing PMM2-CDG.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648315","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

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 4.6 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 4.6 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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis. AAV1。NT3基因治疗减轻多发性硬化症小鼠模型自身免疫性脑脊髓炎的严重程度。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-02-19 DOI: 10.1038/s41434-025-00518-9

Lingying Tong, Burcak Ozes, Kyle Moss, Morgan Myers, Zayed Attia, Tatyana A Vetter, Bruce D Trapp, Zarife Sahenk

{"title":"AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis.","authors":"Lingying Tong, Burcak Ozes, Kyle Moss, Morgan Myers, Zayed Attia, Tatyana A Vetter, Bruce D Trapp, Zarife Sahenk","doi":"10.1038/s41434-025-00518-9","DOIUrl":"https://doi.org/10.1038/s41434-025-00518-9","url":null,"abstract":"Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than 2.5 million patients worldwide. Chronic demyelination in the CNS has an important role in perpetuating axonal loss and increases difficulty in promoting remyelination. Therefore, regenerative, and neuroprotective strategies are essential to overcome this impediment to rescue axonal integrity and function. Neurotrophin 3 (NT-3) has immunomodulatory and anti-inflammatory properties, in addition to its well-recognized function in nervous system development, myelination, neuroprotection, and regeneration. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of experimental autoimmune encephalomyelitis (EAE) mice, the chronic relapsing mouse model of MS, at 3 weeks post EAE induction. Measurable NT-3 levels were found in serum at 7-weeks post gene delivery. The treated cohort showed improved clinical scores and performed significantly better in rotarod, and grip strength tests compared to their untreated counterparts. Histopathologic studies showed improved remyelination and axon protection. These data correlated with reduced expression of the pro-inflammatory cytokines in brain and spinal cord, and increased percentage of regulatory T cells in the spleens and lymph nodes. Collectively, these findings demonstrate the translational potential of AAV-delivered NT-3 for chronic progressive MS.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457602","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