Gene Therapy最新文献_第3页

Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy. 晚期脊髓性肌萎缩患者onasemnogene abparvovec后的致命结果。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-23 DOI: 10.1038/s41434-025-00535-8

Peerada Pongsakornkullachart, Pimchanok Kulsirichawaroj, Ratcharin Kongkasuwan, Prakarn Tovichien, Settapong Jitwongwai, Supaluck Kanjanauthai, Nutnicha Preeprem, Sivaporn Limpaninlachat, Nisasri Sermpon, Oranee Sanmaneechai

{"title":"Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy.","authors":"Peerada Pongsakornkullachart, Pimchanok Kulsirichawaroj, Ratcharin Kongkasuwan, Prakarn Tovichien, Settapong Jitwongwai, Supaluck Kanjanauthai, Nutnicha Preeprem, Sivaporn Limpaninlachat, Nisasri Sermpon, Oranee Sanmaneechai","doi":"10.1038/s41434-025-00535-8","DOIUrl":"https://doi.org/10.1038/s41434-025-00535-8","url":null,"abstract":"Supported by encouraging trial outcomes, onasemnogene abeparvovec (OA) was authorized for spinal muscular atrophy (SMA). Nevertheless, efficacy of OA in advanced SMA patients remains underexplored. This investigation assessed clinical effectiveness and adverse effects of OA in a cohort including advanced SMA, and compared to historical survival data for SMA type 1 patients in Thailand. We conducted observational cohort study at Siriraj Hospital, Thailand, from May 2019 to April 2022. The study enrolled eight SMA patients receiving OA therapy. The cohort comprised five SMA type 1 patients treated at 16.7 months (6.5-24.9 months) and three SMA type 2 patients treated at 20.3 months (19-31.5 months). Before receiving OA, all Type 1 patients required 24-hour invasive ventilation and feeding support. Post-treatment, Three of five showed gradual improvement in motor scores, but none achieved new motor milestones. Survival rate was not improved, with all experiencing fatalities. Conversely, Type 2 patients exhibited motor score improvement without serious adverse events. OA did not significantly improve clinical outcomes or survival rates in advanced Type 1 SMA. These findings highlight need for additional caution when administering OA to severe SMA Type 1 and more specific guidelines in selecting subgroups for treatment.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011513","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

Ex vivo machine perfusion as a platform for lentiviral gene delivery in rat livers. 体外机器灌注作为慢病毒基因在大鼠肝脏传递的平台。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-22 DOI: 10.1038/s41434-025-00536-7

Irina Filz von Reiterdank, Mohammadreza Mojoudi, Raphaela Bento, McLean S Taggart, Antonia T Dinicu, Gregory Wojtkiewicz, J H Coert, Aebele B Mink van der Molen, Ralph Weissleder, Biju Parekkadan, Korkut Uygun

{"title":"Ex vivo machine perfusion as a platform for lentiviral gene delivery in rat livers.","authors":"Irina Filz von Reiterdank, Mohammadreza Mojoudi, Raphaela Bento, McLean S Taggart, Antonia T Dinicu, Gregory Wojtkiewicz, J H Coert, Aebele B Mink van der Molen, Ralph Weissleder, Biju Parekkadan, Korkut Uygun","doi":"10.1038/s41434-025-00536-7","DOIUrl":"https://doi.org/10.1038/s41434-025-00536-7","url":null,"abstract":"Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors encoding the secreted biomarker Gaussia Luciferase (GLuc) and red fluorescent protein (RFP) were introduced ex vivo to rodent livers during a 72-h machine perfusion protocol. After an initial 24-h exposure to viral vectors, the organs were maintained in perfusion for an additional 48 h to monitor gene expression, aligning with in vitro benchmarks. Control livers were perfused in similar fashion, but without viral injections. Virally perfused livers exhibited nearly a 10-fold increase in luminescence compared to controls (p < 0.0001), indicating successful genetic modification of the organs. These findings validate the use of machine perfusion systems and viral vectors to genetically engineer whole organs ex vivo, laying the groundwork for a broad range of applications in transplantation through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical translation.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983866","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

Development of an AAV-RNAi strategy to silence the dominant variant GNAO1 c.607G>A linked to encephalopathy. 开发一种AAV-RNAi策略来沉默与脑病相关的显性变异gnao1c . 607g >a。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-14 DOI: 10.1038/s41434-025-00532-x

Evgenii A Lunev, Natalia V Klementieva, Svetlana G Vassilieva, Egor A Volovikov, David Jappy, Irina M Savchenko, Ekaterina A Svetlova, Anna V Polikarpova, Maria Y Shubina, Danil M Spirin, Ksenia S Anufrieva, Petr R Lebedev, Vladimir M Pokrovsky, Marina V Utkina, Viktoriya G Krut', Mikhail Sintsov, Sergey Popov, Alexey V Deykin, Andrei Rozov, Tatiana V Egorova, Maryana V Bardina

{"title":"Development of an AAV-RNAi strategy to silence the dominant variant GNAO1 c.607G>A linked to encephalopathy.","authors":"Evgenii A Lunev, Natalia V Klementieva, Svetlana G Vassilieva, Egor A Volovikov, David Jappy, Irina M Savchenko, Ekaterina A Svetlova, Anna V Polikarpova, Maria Y Shubina, Danil M Spirin, Ksenia S Anufrieva, Petr R Lebedev, Vladimir M Pokrovsky, Marina V Utkina, Viktoriya G Krut', Mikhail Sintsov, Sergey Popov, Alexey V Deykin, Andrei Rozov, Tatiana V Egorova, Maryana V Bardina","doi":"10.1038/s41434-025-00532-x","DOIUrl":"https://doi.org/10.1038/s41434-025-00532-x","url":null,"abstract":"Heterozygous mutations in GNAO1 cause an ultra-rare neurodevelopmental disease called GNAO1 encephalopathy, characterized by infantile epilepsy and movement disorder. Here, we provide a functional characterization of the hotspot mutation GNAO1 c.607G>A (p.G203R) and conduct early-phase development of an adeno-associated virus (AAV)-mediated gene therapy approach. The GNAO1 gene encodes the Gαo protein that is involved in neuronal signaling. We showed that the Gαo-G203R lost its ability to enhance forskolin-stimulated cAMP synthesis in HEK293T cells. In primary neuronal culture, Gαo-G203R had a dominant-negative effect on neuronal activity and GABAB-dependent synaptic release. To ablate the mutant protein, we used selective silencing of the pathogenic variant using effectors of RNA interference (RNAi). We selected the short hairpin RNA (sh1500) that suppressed the c.607G>A transcripts, resulting in a 3.8-fold increase in the ratio of wild-type to mutant GNAO1 transcripts in patient-specific neurons. We also detected off-target effects of sh1500 as well as transcriptome changes associated with AAV transduction and RNAi activation. We improved the AAV construct by using an artificial miRNA (miR1500) and the neuron-specific hSyn promoter. Systemic administration of AAV9-hSyn-miR1500 did not cause pathological changes in Gnao1-GGA mice with a \"humanized\" target sequence. Importantly, AAV9 transduced Gαo-positive neurons in the striatum, thalamus, substantia nigra, and cerebellum, which we defined as primary targets for gene therapy. Our findings pave the road toward the development of AAV-RNAi approaches for dominant-negative GNAO1 variants.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976401","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

Expression of anti-amyloid CARs in microglia promotes efficient and selective phagocytosis of Aβ1‒42. 小胶质细胞中抗淀粉样蛋白CARs的表达促进了Aβ1-42的有效和选择性吞噬。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-10 DOI: 10.1038/s41434-025-00534-9

Christina N Heiss, Rebecca Riise, Eric Hanse, Stefanie Fruhwürth, Henrik Zetterberg, Andreas Björefeldt

引用次数: 0

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

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 4.6 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