Gene Therapy最新文献

Bridging gene therapy and next-generation vaccine technologies. 连接基因治疗和新一代疫苗技术。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-18 DOI: 10.1038/s41434-024-00502-9

Kristie Bloom, Abdullah Ely, Mohube Betty Maepa, Patrick Arbuthnot

引用次数: 0

Retraction Note: Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. 撤稿说明：使用同时针对视杆细胞和视锥的启动子进行基因治疗，可挽救由AIPL1突变引起的视网膜变性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-15 DOI: 10.1038/s41434-024-00505-6

X Sun, B Pawlyk, X Xu, X Liu, O V Bulgakov, M Adamian, M A Sandberg, S C Khani, M -H Tan, A J Smith, R R Ali, T Li

引用次数: 0

Non-replicative herpes simplex virus genomic and amplicon vectors for gene therapy - an update. 用于基因治疗的非复制性单纯疱疹病毒基因组和扩增子载体--最新进展。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-12 DOI: 10.1038/s41434-024-00500-x

Matthieu Le Hars, Charles Joussain, Teddy Jégu, Alberto L Epstein

{"title":"Non-replicative herpes simplex virus genomic and amplicon vectors for gene therapy - an update.","authors":"Matthieu Le Hars, Charles Joussain, Teddy Jégu, Alberto L Epstein","doi":"10.1038/s41434-024-00500-x","DOIUrl":"https://doi.org/10.1038/s41434-024-00500-x","url":null,"abstract":"Two major types of defective vectors have been derived from herpes simplex virus type 1 (HSV-1), non-replicative genomic vectors (nrHSV-1), and amplicon vectors. This review recapitulates the main features of both vector types and summarizes recent improvements in our understanding of virus/vector biology, particularly with regard to the critical role played by the overpowering of antiviral cellular defenses and the epigenetic control of viral gene expression. Over the past years, significant breakthroughs in vector design, genetic engineering, and HSV-1 biology have accelerated the development of nrHSV-1 vectors. The low immunogenicity and enhanced safety profiles allowed the successful translation of these vectors into several clinical trials, with some being approved by the FDA. Regarding amplicons, despite their advantage in carrying very large or multiple transgenes, and their potential to avoid genome dilution in dividing cells, the absence of production procedures capable of generating large amounts of helper-free amplicons at reasonable cost with GMP compliance, still limits the translation of these outstanding vectors to clinical trials.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618630","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

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

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-11-11 DOI: 10.1038/s41434-024-00501-w

Kristie Bloom

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 : 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":"https://doi.org/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":""},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection 玻璃体内注射 AAV2.7m8 之前和之后绵羊体内抗 AAV2 中和抗体水平的特征。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-10-29 DOI: 10.1038/s41434-024-00495-5

Maya Ross, Kareen Sade, Alexey Obolensky, Edward Averbukh, Melissa Desrosiers, Alexander Rosov, Hay Dvir, Elisha Gootwine, Eyal Banin, Deniz Dalkara, Ron Ofri

{"title":"Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection","authors":"Maya Ross, Kareen Sade, Alexey Obolensky, Edward Averbukh, Melissa Desrosiers, Alexander Rosov, Hay Dvir, Elisha Gootwine, Eyal Banin, Deniz Dalkara, Ron Ofri","doi":"10.1038/s41434-024-00495-5","DOIUrl":"10.1038/s41434-024-00495-5","url":null,"abstract":"Gene augmentation therapy is a promising treatment for incurable, blinding inherited retinal diseases, and intravitreal delivery is being studied as a safe alternative to subretinal injections. Adeno-Associated Viruses (AAV) are commonly-used vectors for ocular gene augmentation therapy. Naturally occurring pre-operative exposure and infection with AAV could result in presence of neutralizing antibodies (NAB’s) in patients’ serum, and may affect the safety and efficacy of treatment. Our aim was to characterize the humoral response against AAV pre- and post-intravitreal delivery of AAV2.7m8 vectors in a naturally-occurring sheep model of CNGA3 achromatopsia. Serial serum neutralization assays were performed to screen sheep for pre-exiting anti-AAV2 NAB’s, and to assess the effect of intravitreal AAV2.7m8 injection on post-operative NAB titers and intraocular inflammation in sheep. The effect of viral dose and transgene type were also assessed. Serological screening revealed pre-operative seropositivity in 21.4% of animals, with age being a risk factor for the presence of anti-AAV2 NAB’s. NAB titers increased following intravitreal AAV administration in the majority of sheep. There was no significant difference in the degree of post-operative serum neutralization between pre-operatively seronegative sheep and those with pre-existing antibodies. However, only sheep with pre-existing antibodies presented with signs of post-operative inflammation. We conclude that pre-existing anti-AAV2 NAB’s do not affect the level of post-operative NAB titers; however, they increase the risk of post-operative ocular inflammation. Our results could have implications for the management of AAV-mediated ocular gene therapies, a technology being increasingly studied and used in patients.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"580-586"},"PeriodicalIF":4.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00495-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545055","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

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 : 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":"https://doi.org/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":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-29","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

The circRNA circSCAF8 promotes tumor growth and metastasis of gastric cancer via miR-1293/TIMP1signaling. circRNA circSCAF8通过miR-1293/TIMP1信号促进胃癌的生长和转移。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-10-27 DOI: 10.1038/s41434-024-00496-4

Bin Mei, Jiajie Chen, Yang Peng

{"title":"The circRNA circSCAF8 promotes tumor growth and metastasis of gastric cancer via miR-1293/TIMP1signaling.","authors":"Bin Mei, Jiajie Chen, Yang Peng","doi":"10.1038/s41434-024-00496-4","DOIUrl":"https://doi.org/10.1038/s41434-024-00496-4","url":null,"abstract":"SR-like CTD-associated factor 8 (SCAF8) can regulate transcriptional termination, but the function of circSCAF8 remains unclear. In our study, we observed a significant increase in circSCAF8 expression in gastric cancer, particularly in tissues with lymph node metastasis. The Kaplan-Meier curve revealed that high circSCAF8 expression was associated with a low overall survival time in gastric cancer patients. Moreover, circSCAF8 shRNA effectively decreased gastric cancer proliferation, invasion, and migration in vitro. Additionally, using bioluminescence imaging (BLI) technology in vivo, we found that circSCAF8 shRNA viruses inhibited the growth of xenograft tumors and gastric cancer lung metastasis. RNA immunoprecipitation (RIP) and circRNA pulldown assays confirmed the direct binding of circSCAF8 to miR-1293, but circSCAF8 could not regulate the expression of miR-1293 in gastric cancer. Interestingly, circSCAF8 regulated the downstream gene tissue inhibitor of metalloproteinases 1 (TIMP1) of miR-1293, and this observation was further verified in gastric cancer tissues. Moreover, we confirmed that miR-1293 directly suppressed TIMP1 expression. Subsequent rescue experiments revealed that TIMP1 overexpression reversed the impact of circSCAF8 shRNA viruses on gastric cancer. In conclusion, circSCAF8 expression was elevated in gastric cancer, and circSCAF8 shRNA viruses inhibited gastric cancer growth and metastasis by upregulating TIMP1 expression via miR-1293.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499059","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

Chemogenetics with PSAM⁴-GlyR decreases excitability and epileptiform activity in epileptic hippocampus. PSAM4-GlyR的化学遗传降低了癫痫海马的兴奋性和痫样活动。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-10-25 DOI: 10.1038/s41434-024-00493-7

Ana Gonzalez-Ramos, Fredrik Berglind, Jan Kudláček, Elza R Rocha, Esbjörn Melin, Ana M Sebastião, Cláudia A Valente, Marco Ledri, My Andersson, Merab Kokaia

{"title":"Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus.","authors":"Ana Gonzalez-Ramos, Fredrik Berglind, Jan Kudláček, Elza R Rocha, Esbjörn Melin, Ana M Sebastião, Cláudia A Valente, Marco Ledri, My Andersson, Merab Kokaia","doi":"10.1038/s41434-024-00493-7","DOIUrl":"https://doi.org/10.1038/s41434-024-00493-7","url":null,"abstract":"Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an \"on-demand\" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499058","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 gene therapy for Duchenne Muscular Dystrophy: lessons learned from a phase 3 trial 杜兴氏肌肉萎缩症的 AAV 基因疗法：从 3 期试验中汲取的经验教训。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-10-23 DOI: 10.1038/s41434-024-00494-6

Giovanni Baranello, Francesco Muntoni

引用次数: 0