Gene Therapy最新文献

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":null,"pages":null},"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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson's disease. 在帕金森病小鼠模型中，靶向血清反应因子（SRF）可使ΔFosB失活并减轻左旋多巴诱发的运动障碍。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-10-09 DOI: 10.1038/s41434-024-00492-8

Piniel Alphayo Kambey, Jiao Wu, WenYa Liu, Mingyu Su, Wokuheleza Buberwa, Chuanxi Tang

{"title":"Targeting serum response factor (SRF) deactivates ΔFosB and mitigates Levodopa-induced dyskinesia in a mouse model of Parkinson's disease.","authors":"Piniel Alphayo Kambey, Jiao Wu, WenYa Liu, Mingyu Su, Wokuheleza Buberwa, Chuanxi Tang","doi":"10.1038/s41434-024-00492-8","DOIUrl":"https://doi.org/10.1038/s41434-024-00492-8","url":null,"abstract":"L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the preferred treatment for Parkinson's Disease (PD) and is considered the gold standard. However, prolonged use of L-DOPA in patients can result in involuntary movements known as Levodopa-induced dyskinesia (LID), which includes uncontrollable dystonia affecting the trunk, limbs, and face. The role of ΔFosB protein, a truncated splice variant of the FosB gene, in LID has been acknowledged, but its underlying mechanism has remained elusive. Here, using a mouse model of Parkinson's disease treated with chronic levodopa we demonstrate that serum response factor (SRF) binds to the FosB promoter, thereby activating FosB expression and levodopa induced-dyskinetic movements. Western blot analysis demonstrates a significant increase in SRF expression in the dyskinetic group compared to the control group. Knocking down SRF significantly reduced abnormal involuntary movements (AIMS) and ΔFosB expression compared to the control. Conversely, overexpression of SRF led to an increase in ΔFosB expression and worsened levodopa-induced dyskinesia. To shed light on the regulatory role of the Akt signaling pathway in this phenomenon, we administered the Akt agonist SC79 to PD mouse models via intraperitoneal injection, followed by L-DOPA administration. The expression of SRF, ΔFosB, and phosphorylated Akt (p-Akt) significantly increased in this group compared to the group receiving normal saline to signify that these happen through Akt signaling pathway. Collectively, our findings identify a promising therapeutic target for addressing levodopa-induced dyskinesia.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389812","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

Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody. 通过 AAV 释放新型抗 Scg3 抗体抑制 matrigel 诱导的脉络膜新生血管。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-27 DOI: 10.1038/s41434-024-00491-9

Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A Webster, Wei Li

{"title":"Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody.","authors":"Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A Webster, Wei Li","doi":"10.1038/s41434-024-00491-9","DOIUrl":"https://doi.org/10.1038/s41434-024-00491-9","url":null,"abstract":"Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block choroidal neovascularization (CNV) induced by subretinal injection of Matrigel in a mouse model. Intravitreal AAV-anti-Scg3Fab significantly reduced CNV and suppressed CNV-associated leukocyte infiltration and macrophage activation. The efficacy and anti-inflammatory effects were equivalent to those achieved by positive control AAV-aflibercept against VEGF. Efficacies of AAV-anti-Scg3Fab and AAV-aflibercept were sustained over 4 months post AAV delivery. The findings support development of AAV-anti-Scg3 as an alternative to AAV-anti-VEGF with equivalent efficacy and potentially safer mechanism of action.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345033","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

Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects. 对新生 ClC-5 基因无效小鼠进行 1 型 Dent 病基因治疗，以获得持续的转基因表达和基因治疗效果。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-25 DOI: 10.1038/s41434-024-00490-w

Pin Lyu, Manish Kumar Yadav, Kyung Whan Yoo, Cuili Jiang, Qingqi Li, Anthony Atala, Baisong Lu

{"title":"Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects.","authors":"Pin Lyu, Manish Kumar Yadav, Kyung Whan Yoo, Cuili Jiang, Qingqi Li, Anthony Atala, Baisong Lu","doi":"10.1038/s41434-024-00490-w","DOIUrl":"https://doi.org/10.1038/s41434-024-00490-w","url":null,"abstract":"Dent disease type 1 is caused by changes in the chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, resulting in the lack or dysfunction of chloride channel ClC-5. Individuals affected by Dent disease type 1 show proteinuria and hypercalciuria. Previously we found that lentiviral vector-mediated hCLCN5 cDNA supplementary therapy in ClC-5 null mice was effective only for three months following gene delivery, and the therapeutic effects disappeared four months after treatment, most likely due to immune responses to the ClC-5 proteins expressed in the treated cells. Here we tried two strategies to reduce possible immune responses: 1) confining the expression of ClC-5 expression to the tubular cells with tubule-specific Npt2a and Sglt2 promoters, and 2) performing gene therapy in newborn mutant mice whose immune system has not fully developed. We found that although Npt2a and Sglt2 promoters successfully drove ClC-5 expression in the kidneys of the mutant mice, the treatment did not ameliorate the phenotypes. However, gene delivery to the kidneys of newborn Clcn5 mutant mice enabled long-term transgene expression and phenotype improvement. Our data suggest that performing gene therapy on Dent disease affected subjects soon after birth could be a promising strategy to attenuate immune responses in Dent disease type 1 gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345031","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

Precision medicine: toward restoring fat with gene therapy in inherited lipodystrophy. 精准医学：利用基因疗法恢复遗传性脂肪营养不良症患者的脂肪。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-24 DOI: 10.1038/s41434-024-00489-3

Xavier Prieur, Lei Cao

引用次数: 0