Gene Therapy最新文献_第2页

Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model. 胎盘纳米颗粒介导的IGF1基因治疗在豚鼠模型中纠正胎儿生长限制。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2024-12-04 DOI: 10.1038/s41434-024-00508-3

Baylea N Davenport, Rebecca L Wilson, Alyssa A Williams, Helen N Jones

{"title":"Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model.","authors":"Baylea N Davenport, Rebecca L Wilson, Alyssa A Williams, Helen N Jones","doi":"10.1038/s41434-024-00508-3","DOIUrl":"10.1038/s41434-024-00508-3","url":null,"abstract":"Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"255-265"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767986","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 : 2025-05-01 Epub 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":" ","pages":"211-222"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","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

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 : 2025-05-01 Epub 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":" ","pages":"287-298"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","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

Expression and distribution of rAAV9 intrathecally administered in juvenile to adolescent mice. rAAV9在幼年至青春期小鼠体内的表达和分布。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2024-11-05 DOI: 10.1038/s41434-024-00498-2

Irvin T Garza, Meghan M Eller, Sydni K Holmes, Morgan K Schackmuth, Rachel M Bailey

{"title":"Expression and distribution of rAAV9 intrathecally administered in juvenile to adolescent mice.","authors":"Irvin T Garza, Meghan M Eller, Sydni K Holmes, Morgan K Schackmuth, Rachel M Bailey","doi":"10.1038/s41434-024-00498-2","DOIUrl":"10.1038/s41434-024-00498-2","url":null,"abstract":"Intrathecal (IT) lumbar puncture delivery of recombinant adeno-associated virus serotype 9 (rAAV9) is a gene therapy approach being explored in preclinical studies and ongoing gene therapy clinical trials for neurological diseases. Few studies address IT rAAV9 vector distribution, tropism, and expression with respect to age of administration. Therefore, we IT delivered a rAAV9/GFP vector in mice at ages ranging from early postnatal development through adulthood (P10-P90). Tissues were assessed for transgene expression, cell tropism, and vector distribution. In the CNS, transduction was highest when delivered at post-natal day 10 (P10) and there was an age-dependent decline in transduction. We found higher transduction of astrocytes relative to neurons when rAAV9 was administered at younger ages and a switch to higher neuronal transduction with delivery at older timepoints. Biodistribution analysis of peripheral tissues showed that when delivered at P10, rAAV9 has the greatest distribution to the heart. Conversely, at P90 rAAV9 liver distribution was highest. As rAAV9 IT-delivered gene therapies continue to emerge for neurological diseases, careful consideration of the age of delivery should be taken in relation to the expected distribution and cell expression in animal models, and how this may translate to human studies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"189-196"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582839","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

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 : 2025-05-01 Epub 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":"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":"184-188"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","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

Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity. 电穿孔介导的新型白蛋白融合 Flt3L DNA 递送可促进 cDC1 相关的抗癌免疫。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-05-01 Epub Date: 2024-10-29 DOI: 10.1038/s41434-024-00497-3

Ming-Hung Hu, Darrell Fan, Hsin-Fang Tu, Ya-Chea Tsai, Liangmei He, Zhicheng Zhou, Michelle Cheng, Deyin Xing, Suyang Wang, Alexis Wu, T C Wu, Chien-Fu Hung

{"title":"Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity.","authors":"Ming-Hung Hu, Darrell Fan, Hsin-Fang Tu, Ya-Chea Tsai, Liangmei He, Zhicheng Zhou, Michelle Cheng, Deyin Xing, Suyang Wang, Alexis Wu, T C Wu, Chien-Fu Hung","doi":"10.1038/s41434-024-00497-3","DOIUrl":"10.1038/s41434-024-00497-3","url":null,"abstract":"Dendritic cells (DCs) constitute a distinct type of immune cell found within tumors, serving a central role in mediating tumor antigen-specific immunity against cancer cells. Frequently, DC functions are dysregulated by the immunosuppressive signals present within the tumor microenvironment (TME). Consequently, DC manipulation holds great potential to enhance the cytotoxic T cell response against cancer diseases. One strategy involves administering Fms-like tyrosine kinase receptor 3 ligand (Flt3L), a vitally important cytokine for DC development. In this current study, the electroporation-mediated delivery of a novel albumin-fused Flt3L DNA (alb-Flt3L DNA) demonstrated the ability to induce an anti-tumor immune response. This albumin fusion construct possesses more persistent bioactivity in targeted organs. Furthermore, TC-1-bearing-C57BL/6 mice receiving alb-Flt3L DNA treatment presented better tumor control and superior survival. Cellular analysis revealed that alb-Flt3L DNA administration promoted robust DC and cDC1 expansion. In addition, increased levels of IFN-γ-secreting CD8+ lymphocytes were found in correlation to greater cDC1 population. Moreover, the toxicity of alb-Flt3L administration is limited. Collectively, our data showcases a novel DC-based immunotherapy using electroporation to administer alb-Flt3L DNA.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":"277-286"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545056","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 : 2025-05-01 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

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 : 2025-05-01 Epub 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":" ","pages":"197-210"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","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

A novel multi-functional chimeric peptide for enhanced safe gene delivery in immunotherapy. 一种新型多功能嵌合肽增强免疫治疗中基因的安全传递。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-30 DOI: 10.1038/s41434-025-00538-5

Mahdiyar Dehshiri, Shokouh Rezaei, Saman Hosseinkhani

{"title":"A novel multi-functional chimeric peptide for enhanced safe gene delivery in immunotherapy.","authors":"Mahdiyar Dehshiri, Shokouh Rezaei, Saman Hosseinkhani","doi":"10.1038/s41434-025-00538-5","DOIUrl":"https://doi.org/10.1038/s41434-025-00538-5","url":null,"abstract":"Chimeric peptides hold promising potential to be introduced as an ideal gene delivery platform based on their advantages over viral carriers, including but not limited to the safety profile and specific targeting. However, their gene transfer efficiency needs improvement. Here, we designed a new multi-functional chimeric peptide for enhanced gene delivery by adding a cyclic TAT motif to a previously designed MPG2H peptide to enable the targeting of cells with independent/dependent endocytosis cell entry mechanisms. CTATMPG2H was expressed and purified using affinity chromatography; then it was characterized through a gel retardation assay, circular dichroism (CD) spectropolarimetry, transmission electron microscopy (TEM) dynamic light scattering (DLS), and zeta potential analysis. CTATMPG2H was compared with MiRGD as a chimeric peptide control in all steps. After assessing the platform stability in various conditions, its gene transfer efficiency was evaluated in the HEK293T cell line with reporter genes. Additionally, mouse bone marrow-derived dendritic cells (BMDCs) were transfected to test CTATMPG2H potential in immunotherapy. The results illustrated a safe gene transfer profile for CTATMPG2H comparable to MiRGD and Polyethyleneimine (PEI). Flow cytometry results showed up to 48% gene transfer rate for CTATMPG2H to dendritic cells with minimal toxicity (viability rate ~80%). Moreover, the in silico investigation showed that the synergistic effects of electrostatic, hydrogen, and hydrophobic interactions enhance the stability and binding affinity of peptide-pDNA complexes, ensuring robust and specific targeting of nucleic acids. This research sets a foundation for future in vivo studies and potential clinical applications, aiming for safer and more effective gene therapy strategies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002900","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

From bench to bedside: the future of stable lentiviral packaging cell lines in gene therapy. 从实验室到床边：基因治疗中稳定慢病毒包装细胞系的未来。

IF 4.6 3区医学

Gene Therapy Pub Date : 2025-04-26 DOI: 10.1038/s41434-025-00537-6

Kumitaa Theva Das

引用次数: 0