{"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":"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":"31 11-12","pages":"614-624"},"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}
Gene TherapyPub Date : 2024-09-27DOI: 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":"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":"31 11-12","pages":"587-593"},"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}
Gene TherapyPub Date : 2024-09-25DOI: 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":"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":"31 11-12","pages":"563-571"},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00490-w.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"BRD9 promotes the progression of gallbladder cancer via CST1 upregulation and interaction with FOXP1 through the PI3K/AKT pathway and represents a therapeutic target","authors":"Jing Qiang, Cheng Zhao, Liu-Qing Shi, Si-Rui Sun, Hua-Kai Wang, Shi-Lei Liu, Zi-Yi Yang, Ping Dong, Shan-Shan Xiang, Jian-Dong Wang, Yi-Jun Shu","doi":"10.1038/s41434-024-00488-4","DOIUrl":"10.1038/s41434-024-00488-4","url":null,"abstract":"Gallbladder cancer (GBC) is highly aggressive and has poor prognosis, with most patients only diagnosed at an advanced stage. Furthermore, treatment options are limited, and their effect is unsatisfactory. Bromodomain-containing protein (BRD) is an epigenetic regulator that plays a carcinogenic role in several tumors, including squamous cell lung cancer, acute myeloid leukemia, synovial sarcoma, and malignant rhabdomyosarcoma. However, the expression, biological function, and molecular mechanisms of action of BRD9 in GBC are still unknown. Kaplan–Meier analysis, qRT-PCR, and analysis of clinical features were used to assess the clinical significance of BRD9 in GBC. Cell Counting Kit-8 and colony formation assays were performed to determine the effects of BRD9 on cell growth. The functional role of BRD9 in GBC was explored using qRT-PCR, western blotting, siRNA, and CHIP-qPCR. mRNA sequencing was performed to explore the underlying mechanisms of BRD9, and a nude mouse model of GBC was established to explore the anti-tumor effects of the BRD9 inhibitor I-BRD9 in vivo. BRD9 expression was elevated in GBC tissues compared with adjacent non-tumor tissues, and high BRD9 expression was associated with poor prognosis in patients with GBC. BRD9 knockdown by siRNA significantly decreased cell growth. Targeting BRD9 with I-BRD9 inhibited the proliferation of GBC cells without significant toxic effects. Additionally, I-BRD9 treatment suppressed CST1 expression in GBC cell lines, thereby inhibiting the PI3K-AKT pathway. The transcription factor FOXP1 was found to interact with BRD9 to regulate CST1 expression. Collectively, these results suggest that BRD9 may be a promising biomarker and therapeutic target for GBC.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"594-606"},"PeriodicalIF":4.6,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00488-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284337","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}
Gene TherapyPub Date : 2024-09-18DOI: 10.1038/s41434-024-00482-w
Sujun Li, Shyamtanu Datta, Emily Brabbit, Zoe Love, Victoria Woytowicz, Kyle Flattery, Jessica Capri, Katie Yao, Siqi Wu, Michael Imboden, Arun Upadhyay, Rasappa Arumugham, Wallace B. Thoreson, Margaret M. DeAngelis, Neena B. Haider
{"title":"Correction: Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa","authors":"Sujun Li, Shyamtanu Datta, Emily Brabbit, Zoe Love, Victoria Woytowicz, Kyle Flattery, Jessica Capri, Katie Yao, Siqi Wu, Michael Imboden, Arun Upadhyay, Rasappa Arumugham, Wallace B. Thoreson, Margaret M. DeAngelis, Neena B. Haider","doi":"10.1038/s41434-024-00482-w","DOIUrl":"10.1038/s41434-024-00482-w","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"630-632"},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00482-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284338","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}
{"title":"Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice","authors":"Feixu Zhang, Xinyue Zhou, Baolai Hua, Xinyi He, Zhanao Li, Xiao Xiao, Xia Wu","doi":"10.1038/s41434-024-00479-5","DOIUrl":"10.1038/s41434-024-00479-5","url":null,"abstract":"In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"544-552"},"PeriodicalIF":4.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00479-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212559","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}
Gene TherapyPub Date : 2024-09-09DOI: 10.1038/s41434-024-00475-9
Da-Wei Yang, Gui-Bin Qian, Ming-Jiu Jiang, Peng Wang, Kun-Zheng Wang
{"title":"Retraction Note: Inhibition of microRNA-495 suppresses chondrocyte apoptosis through activation of the NF-κB signaling pathway by regulating CCL4 in osteoarthritis","authors":"Da-Wei Yang, Gui-Bin Qian, Ming-Jiu Jiang, Peng Wang, Kun-Zheng Wang","doi":"10.1038/s41434-024-00475-9","DOIUrl":"10.1038/s41434-024-00475-9","url":null,"abstract":"","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"625-625"},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00475-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284339","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}
Gene TherapyPub Date : 2024-09-05DOI: 10.1038/s41434-024-00485-7
Qi Lu, Anna Wright, Zhuo-Hua Pan
{"title":"AAV dose-dependent transduction efficiency in retinal ganglion cells and functional efficacy of optogenetic vision restoration","authors":"Qi Lu, Anna Wright, Zhuo-Hua Pan","doi":"10.1038/s41434-024-00485-7","DOIUrl":"10.1038/s41434-024-00485-7","url":null,"abstract":"Optogenetics is a promising approach for restoring vision to the blind after photoreceptor degeneration. The ability to restore vision through AAV-mediated delivery of light-sensitive proteins, especially channelrhodopsins, into retinal ganglion cells has been extensively demonstrated in animal models. For clinical application, knowledge of viral dose-dependent functional efficacy is desired. In this study, using a triple-knockout blind mouse model and a highly light-sensitive channelrhodopsin variant, we evaluated viral dose-dependent vision restoration through retinal ganglion cell expression by using optomotor behavioral assays. Our results show that both the restored light sensitivity and visual acuity reached peak levels at a medial viral dose of 108 vg. With increasing dose, transduction efficiency continued to increase while protein expression peaked at the dose of ~109 vg and declined at higher doses. Also, a significant increase in retinal gliosis and inflammatory responses started at the dose of ~109 vg, and a marked increase was observed at the dose of ~1010. These results provide valuable insights into viral dose design for clinical studies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"572-579"},"PeriodicalIF":4.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00485-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139949","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}