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New paradigms to break barriers in early cancer detection for improved prognosis and treatment outcomes 打破早期癌症检测障碍,改善预后和治疗效果的新模式
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-17 DOI: 10.1002/jgm.3730
Irfan Ahmad, Saade Abdalkareem Jasim, M. K. Sharma, Renuka Jyothi S, Ahmed Hjazi, Jaafaru Sani Mohammed, Aashna Sinha, Ahmed Hussein Zwamel, Hamza Fadhel Hamzah, Bahira Abdulrazzaq Mohammed

The uncontrolled growth and spread of cancerous cells beyond their usual boundaries into surrounding tissues characterizes cancer. In developed countries, cancer is the leading cause of death, while in underdeveloped nations, it ranks second. Using existing cancer diagnostic tools has increased early detection rates, which is crucial for effective cancer treatment. In recent decades, there has been significant progress in cancer-specific survival rates owing to advances in cancer detection and treatment. The ability to accurately identify precursor lesions is a crucial aspect of effective cancer screening programs, as it enables early treatment initiation, leading to lower long-term incidence of invasive cancer and improved overall prognosis. However, these diagnostic methods have limitations, such as high costs and technical challenges, which can make accurate diagnosis of certain deep-seated tumors difficult. To achieve accurate cancer diagnosis and prognosis, it is essential to continue developing cutting-edge technologies in molecular biology and cancer imaging.

癌细胞不受控制地生长并向周围组织扩散,这就是癌症的特征。在发达国家,癌症是导致死亡的主要原因,而在不发达国家,癌症则位居第二。利用现有的癌症诊断工具提高了早期发现率,这对有效治疗癌症至关重要。近几十年来,由于癌症检测和治疗的进步,癌症患者的生存率有了显著提高。准确识别前驱病变的能力是有效癌症筛查计划的一个重要方面,因为它能使治疗尽早开始,从而降低浸润性癌症的长期发病率并改善总体预后。然而,这些诊断方法都有其局限性,例如成本高昂和技术难度大,因此很难准确诊断某些深部肿瘤。要实现准确的癌症诊断和预后,必须继续开发分子生物学和癌症成像方面的尖端技术。
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引用次数: 0
RNF43 in cancer: Molecular understanding and clinical significance in immunotherapy 癌症中的 RNF43:对免疫疗法的分子认识和临床意义。
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-15 DOI: 10.1002/jgm.3729
Xingfa Huo, Weizhong Han, Zhen Yang, Yongzhi Lu, Ning Liu, Helei Hou

Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumor mutational burden reportedly tend to respond to ICIs. Therefore, the original function of neoantigenic mutations and their impact on the tumor microenvironment (TME) require attention. RNF43 is a type of RING E3 ubiquitin ligase, and long-term survivors in most cancers had conserved patterns of mutations of RNF43. Also, high microsatellite instability patients had a higher RNF43 mutation rate compared with microsatellite stability tumor patients, who were more sensitive to ICI treatment. Therefore, RNF43 has become a promising biomarker of immunotherapy in a wide range of cancers. This review focuses on the up-to-date knowledge of RNF43 mutation in cancer. We summarize the cancer hallmarks involving activities regulated by RNF43 and highlight its extremely sophisticated regulation of WNT signaling and tumor microenvironment. The key genes interacting with RNF43 have also been summarized and discussed. Additionally, we highlight and propose new strategies of targeting RNF43 and RNF43-based combinations with established immunotherapy and combination therapy. These efforts may provide new perspectives for RNF43-based target therapy in cancer.

有必要找出预测免疫检查点抑制剂(ICI)疗效的生物标志物。据报道,考虑到体细胞突变衍生的新抗原会诱导强烈的免疫反应,肿瘤突变负荷高的患者往往会对 ICIs 产生反应。因此,需要关注新抗原突变的原始功能及其对肿瘤微环境(TME)的影响。RNF43是一种RING E3泛素连接酶,大多数癌症的长期存活者都有RNF43突变的保守模式。此外,与微卫星稳定性肿瘤患者相比,高微卫星不稳定性患者的RNF43突变率更高,而后者对ICI治疗更敏感。因此,RNF43已成为多种癌症免疫疗法的一个有前途的生物标志物。本综述主要介绍癌症中 RNF43 基因突变的最新知识。我们总结了涉及 RNF43 调控活动的癌症特征,并强调了它对 WNT 信号转导和肿瘤微环境的极其复杂的调控。我们还总结并讨论了与 RNF43 相互作用的关键基因。此外,我们还强调并提出了针对 RNF43 的新策略,以及基于 RNF43 与现有免疫疗法和联合疗法的组合。这些努力可能会为基于 RNF43 的癌症靶向治疗提供新的视角。
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引用次数: 0
Building endoplasmic reticulum stress-related LncRNAs signatures of lung adenocarcinoma 构建肺腺癌的内质网应激相关 LncRNAs 特征
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-15 DOI: 10.1002/jgm.3731
Kai Chen, Peiling Dai, Lizhong Gu

Background

Endoplasmic reticulum stress (ERS) could be a strategy for treating malignant tumors. Moreover, long noncoding RNAs (lncRNAs) can promote tumorigenesis and progression, and forecast the prognosis of cancers. Nevertheless, the prognostic value of ERS-related lncRNAs has not been reported in lung adenocarcinoma (LUAD).

Methods

The messenger RNA (mRNA), microRNA (miRNA) and lncRNA expression data related to LUAD were obtained in public databases (TCGA and GEO databases). Prognostic ERS-related differentially expressed lncRNAs (ERS-DELs) were obtained and used to build an ERS-related model by Cox regression analysis. Moreover, we further screened independent prognostic elements and built a nomogram. Furthermore, enrichment analysis of genes was conducted to investigate the functions. A lncRNA–miRNA–mRNA network was built to explore mechanism of lncRNAs. Finally, qRT-PCR was utilized to examine the expression levels of lncRNAs.

Results

30 ERS-DELs were identified, and an ERS-related signature was built based on AF131215.2, LINC00472, LINC01352, RP1-78O14.1, RP11-253E3.3, RP11-98D18.9, and SNHG12. Gene set enrichment analysis indicated that genes in the high-risk group were chiefly focused on the regulation of mRNA binding, and genes in the low-risk group were significantly focused on protein localization to cilia. A lncRNA–miRNA–mRNA network, containing 7 signature lncRNAs, 23 miRNAs, and 128 mRNAs, was also established. Eventually, quantitative real-time polymerase chain reaction was used to confirm that seven prognostic lncRNAs had a consistent expression with the analysis.

Conclusions

An ERS-related signature containing seven prognostic lncRNAs was built, which offered new thinking concerning the role of ERS-related lncRNAs in LUAD.

背景:内质网应激(ERS)可能是治疗恶性肿瘤的一种策略。此外,长非编码 RNA(lncRNA)可促进肿瘤的发生和发展,并预测癌症的预后。然而,肺腺癌(LUAD)中与ERS相关的lncRNAs的预后价值尚未见报道:方法:从公共数据库(TCGA 和 GEO 数据库)中获取与 LUAD 相关的信使 RNA(mRNA)、microRNA(miRNA)和 lncRNA 表达数据。通过Cox回归分析,获得了预后性ERS相关的差异表达lncRNAs(ERS-DELs),并用于建立ERS相关模型。此外,我们还进一步筛选了独立的预后要素,并建立了一个提名图。此外,我们还对基因进行了富集分析,以研究其功能。我们建立了一个 lncRNA-miRNA-mRNA 网络,以探索 lncRNA 的作用机制。最后,利用qRT-PCR检测了lncRNAs的表达水平:结果:发现了30个ERS-DELs,并根据AF131215.2、LINC00472、LINC01352、RP1-78O14.1、RP11-253E3.3、RP11-98D18.9和SNHG12建立了ERS相关特征。基因组富集分析表明,高风险组的基因主要集中在 mRNA 结合的调控上,而低风险组的基因则主要集中在纤毛蛋白质定位上。此外,还建立了一个包含7个特征性lncRNA、23个miRNA和128个mRNA的lncRNA-miRNA-mRNA网络。最后,研究人员利用定量实时聚合酶链反应证实,7个预后lncRNA的表达与分析结果一致:结论:建立了包含7个预后lncRNA的ERS相关特征,为ERS相关lncRNA在LUAD中的作用提供了新思路。
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引用次数: 0
Novel co-delivery of oridonin and docetaxel nanoliposome for an enhanced antitumor effect on esophageal cancer 新型奥利多宁和多西他赛纳米脂质体联合给药增强食管癌的抗肿瘤效果
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-12 DOI: 10.1002/jgm.3725
Xi Chen, Hengyu Mao, Feng Peng, Jiang Fan, Fu Yang

Introduction

Esophageal cancer is one of the major cancers in China. Most patients with esophageal cancer are diagnosed at an advanced stage, and the 5 year survival rate is discouraging. Combined chemotherapy is a common method for the treatment of esophageal cancer.

Methods

In this study, distearoyl phosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000) nanoliposomes (NLPs) encapsulating the anticancer drugs docetaxel (DOX) and oridonin (ORD) were prepared, and their ability to enhance the release of anticancer drugs was determined. The NLP system was characterized by transmission electron microscopy, particle size and encapsulation efficiency. In addition, the release characteristics and pharmacodynamics of these drugs were also studied in detail.

Results

When the DOX/ORD ratio was 2:1, the higher proportion of DOX led to a stronger synergy effect. DOX/ORD NLPs were prepared by the high-pressure homogenization method and had a uniform spherical morphology. The mean particle size and polydispersity index were determined to be 246.4 and 0.163, respectively. The stability results showed that no significant change was observed in particle size, zeta potential, Encapsulation efficiency and dynamic light scattering for DOX/ORD NLPs during the observation period. The results of in vitro release illustrated that the acidic environment of tumor might be beneficial to drug release. The three-dimensional tumorsphere showed that DOX/ORD NLPs can reach the interior of tumor spheres, which destroys the structure of cells, resulting in irregular spherical tumor spheres. The in vivo study results indicated that DOX/ORD NLPs had an obvious targeting effect on subcutaneous tumors and have the potential to actively deliver drugs to tumor tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect apoptosis. The results showed that DOX/ORD NLP treatment could significantly induce apoptosis and inhibit tumor growth.

Conclusion

The DOX/ORD NLPs prepared in this study can enhance the anti-tumor activity, and are expected to be a promising co-delivery platform for the treatment of esophageal cancer.

简介食管癌是中国的主要癌症之一。大多数食管癌患者确诊时已是晚期,5 年生存率令人沮丧。联合化疗是治疗食管癌的常用方法:本研究制备了包裹抗癌药物多西他赛(DOX)和奥利多宁(ORD)的二硬脂酰磷脂酰乙醇胺聚乙二醇 2000(DSPE-PEG2000)纳米脂质体(NLPs),并测定了其增强抗癌药物释放的能力。通过透射电子显微镜、粒度和封装效率对 NLP 系统进行了表征。此外,还详细研究了这些药物的释放特性和药效学:结果:当 DOX/ORD 的比例为 2:1 时,DOX 的比例越高,协同效应越强。采用高压均质法制备的 DOX/ORD NLPs 具有均匀的球形形态。平均粒径和多分散指数分别为 246.4 和 0.163。稳定性结果表明,在观察期内,DOX/ORD NLPs 的粒度、ZETA电位、包封效率和动态光散射均无明显变化。体外释放结果表明,肿瘤的酸性环境可能有利于药物的释放。三维肿瘤球显示,DOX/ORD NLPs能到达肿瘤球内部,破坏细胞结构,形成不规则球形肿瘤球。体内研究结果表明,DOX/ORD NLPs 对皮下肿瘤有明显的靶向作用,具有向肿瘤组织主动递送药物的潜力。末端脱氧核苷酸转移酶dUTP缺口标记(TUNEL)染色用于检测细胞凋亡。结果表明,DOX/ORD NLP处理可显著诱导细胞凋亡并抑制肿瘤生长:结论:本研究制备的 DOX/ORD NLPs 可增强抗肿瘤活性,有望成为治疗食管癌的联合给药平台。
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引用次数: 0
RETRACTION: Long non-coding RNA KCNQ1OT1 Promotes the Progression of Gastric Cancer via the miR-145-5p/ARF6 Axis 回归:长非编码 RNA KCNQ1OT1 通过 miR-145-5p/ARF6 轴促进胃癌进展
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-08 DOI: 10.1002/jgm.3727

RETRACTION: X. Zhong, X. Wen, L. Chen, N. Gu, X. Yu, and K. Sui, “Long non-coding RNA KCNQ1OT1 Promotes the Progression of Gastric Cancer via the miR-145-5p/ARF6 Axis,” The Journal of Gene Medicine 23, no. 5 (2021): e3330, https://doi.org/10.1002/jgm.3330.

The above article, published online on 8 March 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Jiang Fan; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Specifically, multiple image elements were found to have been published elsewhere in a different scientific context. Furthermore, the article presents results from multiple non-verifiable/unknown cell lines: BSG823, BSG803, BGC803, and GSE1. Accordingly, the conclusions of this article are considered invalid by the editors. The authors have been informed of the decision of retraction but unavailable for a final confirmation.

退稿:X. Zhong, X. Wen, L. Chen, N. Gu, X. Yu, and K. Sui, "Long non-coding RNA KCNQ1OT1 Promotes the Progression of Gastric Cancer via the miR-145-5p/ARF6 Axis," The Journal of Gene Medicine 23, no.5 (2021): e3330, https://doi.org/10.1002/jgm.3330.The 上述文章于 2021 年 3 月 8 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),经期刊主编 Jiang Fan 和 John Wiley & Sons Ltd.同意,已被撤回。之所以同意撤稿,是因为第三方对文章中提供的数据提出了疑虑。我们发现,文章所展示的结果与实验方法之间存在若干缺陷和不一致之处。具体而言,发现多个图像元素已在其他地方的不同科学背景下发表。此外,文章还介绍了多个不可验证/未知细胞系的结果:BSG823、BSG803、BGC803 和 GSE1。因此,编辑认为这篇文章的结论无效。作者已被告知撤稿决定,但无法得到最终确认。
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引用次数: 0
The mechanism of lovastatin in suppressing the proliferation of esophageal squamous cell carcinoma based on proteomics 基于蛋白质组学研究洛伐他汀抑制食管鳞癌增殖的机制
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-08 DOI: 10.1002/jgm.3722
Feng Peng, Lili Zhu, Jiang Fan, Fu Yang

Background

Lovastatin, a type of statin usually considered as a lipid-lowering drug that lowers blood cholesterol and low-density lipoprotein cholesterol levels, has been rediscovered to have anticancer activity. Fewer studies exist regarding the effect of lovastatin on esophageal squamous cell carcinoma (ESCC).

Methods

Here, we report that lovastatin shows anticancer effect on ESCC By affecting the mitochondrial autophagy pathway. Moreover, based on proteomics and computer molecular simulations found that RAB38 and RAB27A may be a target of lovastatin.

Results

We observed that autophagy of mitochondria is inhibited by lovastatin, affecting esophageal squamous cell proliferation. There is a possible link between the expression of RAB38, RAB27A and immune cell invasion in esophageal cancer.

Conclusions

These results demonstrate the huge potential of lovastatin as an RAB38, RAB27A inhibitor in esophageal cancer chemotherapy and chemoprevention.

背景:洛伐他汀是一种他汀类药物,通常被认为是一种降脂药物,可降低血液中胆固醇和低密度脂蛋白胆固醇的水平。方法:在此,我们报告了洛伐他汀通过影响线粒体自噬途径对食管鳞状细胞癌(ESCC)的抗癌作用。此外,基于蛋白质组学和计算机分子模拟发现,RAB38和RAB27A可能是洛伐他汀的靶点:结果:我们观察到洛伐他汀抑制了线粒体的自噬,从而影响了食管鳞状细胞的增殖。RAB38、RAB27A的表达与食管癌免疫细胞侵袭之间可能存在联系:这些结果表明,洛伐他汀作为一种 RAB38、RAB27A 抑制剂,在食管癌化疗和化学预防方面具有巨大潜力。
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引用次数: 0
Gene therapy clinical trials worldwide to 2023—an update 到 2023 年全球基因治疗临床试验的最新情况。
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-08 DOI: 10.1002/jgm.3721
Samantha L. Ginn, Mawj Mandwie, Ian E. Alexander, Michael Edelstein, Mohammad R. Abedi

To date, 3,900 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our March 2023 update, we have entries on 3,900 trials undertaken in 46 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at https://a873679.fmphost.com/fmi/webd/GTCT. We also provide an overview of the progress being made around the world, and discuss key trends since the previous review, namely the unprecedented increase in gene therapy clinical trial activity, including the implementation of genome editing technology with the potential to transform the field moving forward.

迄今为止,全球共有 3,900 项基因治疗临床试验已经完成、正在进行或已获批准。我们的数据库汇集了全球基因治疗临床活动的相关信息,这些信息来自试验数据库、官方机构资料来源、出版文献、会议演讲以及由研究者个人或试验赞助商慷慨提供给我们的海报。本综述介绍了我们对据我们所知全球已经或正在进行的临床试验的分析。截至 2023 年 3 月的更新,我们已经掌握了 46 个国家/地区开展的 3,900 项试验的条目。我们分析了试验的地理分布、试验的疾病适应症(或其他原因)、使用不同载体类型的比例以及转移了哪些基因。有关分析的详情以及我们的可搜索数据库,请访问《基因医学杂志》的全球基因治疗临床试验网站 https://a873679.fmphost.com/fmi/webd/GTCT。我们还概述了世界各地取得的进展,并讨论了自上次回顾以来的主要趋势,即基因治疗临床试验活动的空前增加,包括基因组编辑技术的实施,该技术有可能改变这一领域的发展。
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引用次数: 0
PDCL3 as a prognostic factor and associated with the VEGF signaling pathway in glioma PDCL3是胶质瘤的预后因子,与血管内皮生长因子信号通路相关。
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-08-06 DOI: 10.1002/jgm.3724
Bo Yang, Guangwei Zheng, Feng Lu

Background

New targeted drugs about angiogenesis could develop the treatment of glioma. We aimed to explore the role of phosducin like 3 (PDCL3) in angiogenesis of glioma.

Materials and Methods

RNA sequencing data and matched clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To screen for the reliable genes with the filtering analyses, survival, multivariate Cox, receiver operating characteristic (ROC) curve filtration, and clinical correlation analyses were performed. The PDCL3 gene was validated by immunohistochemistry as a reliable gene for further analysis. Then we used the combined data of TCGA and Genotype-Tissue Expression from UCSC to detect the differential gene expression of PDCL3. Related signal pathways in glioma were explored by the gene set enrichment analysis and co-expression analysis. Lastly, we performed in vitro experiments to verify the gene functions and related mechanisms.

Results

The three filtering analyses and immunostaining indicated that the expression of PDCL3 in glioma tissues was higher than the normal tissues. Gene function analysis showed that PDCL3 activated the vascular endothelial growth factor (VEGF) signal pathway, and its mechanism was related to pathways in cancer, like NOD like receptor signaling pathway, the RIG-I like receptor signaling pathway and the P53 signaling pathway by MAPK/AKT in gliomas. This suggested that the proliferation, migration and invasion of glioma cells might be inhibited by the downregulation of PDCL3 in vitro, which may be related to the activation of VEGF signaling pathway.

Conclusion

We demonstrated that PDCL3 could function as an independent adverse prognostic marker in glioma. Its pro-oncogenic mechanism may be related to the VEGF signaling pathway.

背景:有关血管生成的新靶向药物可促进胶质瘤的治疗。我们的目的是探讨类磷脂蛋白3(PDCL3)在胶质瘤血管生成中的作用:从癌症基因组图谱(The Cancer Genome Atlas,TCGA)和中国胶质瘤基因组图谱(Chinese Glioma Genome Atlas,CGGA)数据库下载RNA测序数据和匹配的临床数据。为筛选出可靠的基因,进行了生存分析、多变量 Cox 分析、接收者操作特征曲线(ROC)筛选分析和临床相关性分析。经免疫组化验证,PDCL3基因是进一步分析的可靠基因。然后,我们利用 TCGA 和 UCSC 的基因型-组织表达联合数据检测了 PDCL3 的差异基因表达。通过基因组富集分析和共表达分析,我们探索了胶质瘤中的相关信号通路。最后,我们进行了体外实验来验证基因的功能和相关机制:结果:三种筛选分析和免疫染色表明,PDCL3在胶质瘤组织中的表达高于正常组织。基因功能分析表明,PDCL3能激活血管内皮生长因子(VEGF)信号通路,其机制与肿瘤中的通路有关,如胶质瘤中的NOD样受体信号通路、RIG-I样受体信号通路和MAPK/AKT的P53信号通路。这表明,体外下调PDCL3可抑制胶质瘤细胞的增殖、迁移和侵袭,这可能与血管内皮生长因子信号通路的激活有关:结论:我们的研究表明,PDCL3可作为胶质瘤独立的不良预后标志物。结论:我们的研究表明,PDCL3可作为胶质瘤的独立不良预后标志物,其促癌机制可能与血管内皮生长因子信号通路有关。
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引用次数: 0
Safety of intravitreally delivered AAV2 vector-mediated multi-characteristic opsin genetic construct in wild type beagle dogs 在野生型小猎犬体内静脉注射 AAV2 向量介导的多特征蛋白基因构建物的安全性。
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-23 DOI: 10.1002/jgm.3720
Samarendra Mohanty, Subrata Batabyal, Ananta Ayyagari, Najam A. Sharif

Background

A novel adeno-associated virus 2 (AAV2)-carried multi-characteristic opsin (MCO) (MCO-010) is undergoing several clinical trials as a novel therapeutic modality for the treatment of degenerative retinal diseases including retinitis pigmentosa and Stargardt disease. The present study aimed to determine the ocular and systemic safety of MCO-010 and the AAV2 vehicle in adult Beagle dogs following intravitreal (IVT) injection.

Methods

The current safety/toxicology studies spanning 13 weeks described here utilized well-documented techniques to assess the effects of IVT injection of MCO-010 up to 2.2 × 1011 genome copies (gc) per eye, or the AAV2 capsid (vehicle control) on gross behavioral and immunogenic changes, alterations in body weights, blood biochemistry, hematology, blood coagulation, gross necropsy lesions, organ weight changes and histopathology in the dogs (n = 4 per group; two males and two females per group). Immunohistochemical and functional electroretinogram studies were also conducted to determine MCO expression in the retina and determine any retinal toxicity associated with MCO-010.

Results

There were no significant deleterious effects of the MCO-010 (or the AAV2 at the tested doses) on any of the examined parameters, including the absence of any severe ocular or systemic adverse events. However, as expected, inflammation after IVT delivery of AAV2 and MCO-010 was observed in the conjunctivae of all groups of animals, although this self-resolved within 1 week post-injection. Quantitative immunohistochemical analyses of MCO-010-associated mCherry revealed successful delivery of the gene therapy within the inner retina.

Conclusions

In summary, MCO-010 demonstrated a favorable safety profile when administered to the eyes of adult Beagle dogs of both sexes at dose levels up to 2.2 × 1011 gc per eye, with no adverse effects observed. This dose was identified as the No Observed Adverse Effect Level (i.e. NOAEL) and guided selection of safe doses for human clinical trials.

背景:一种新型腺相关病毒2(AAV2)携带的多特性视蛋白(MCO)(MCO-010)正在进行多项临床试验,它是治疗视网膜变性疾病(包括视网膜色素变性和Stargardt病)的一种新型治疗方法。本研究旨在确定 MCO-010 和 AAV2 载体在成年比格犬体内静脉注射后的眼部和全身安全性:本文所述的安全性/毒理学研究时间跨度为 13 周,采用的是有据可查的技术来评估 IVT 注射 MCO-010 的影响,最高剂量为 2.2 × 1011 个基因组拷贝 (gc) 或 AAV2 包膜(载体对照)对狗(每组 4 只;每组 2 只雌雄狗)行为和免疫原性变化、体重变化、血液生化、血液学、血液凝固、尸检病变、器官重量变化和组织病理学的影响。还进行了免疫组化和功能性视网膜电图研究,以确定视网膜中 MCO 的表达,并确定 MCO-010 是否对视网膜产生毒性:结果:MCO-010(或测试剂量的AAV2)对任何检查参数都没有明显的有害影响,包括没有出现任何严重的眼部或全身不良反应。不过,正如预期的那样,所有组别动物的结膜在静脉注射 AAV2 和 MCO-010 后都出现了炎症,不过这种炎症在注射后一周内自行消退。对 MCO-010 相关 mCherry 的定量免疫组化分析表明,基因疗法成功地在视网膜内层传递:总之,MCO-010在对成年比格犬(雌雄均可)的眼睛进行注射时表现出良好的安全性,每只眼睛的注射剂量最高可达2.2 × 1011 gc,且未观察到任何不良反应。该剂量被确定为未观察到不良反应水平(即 NOAEL),为人体临床试验选择安全剂量提供了指导。
{"title":"Safety of intravitreally delivered AAV2 vector-mediated multi-characteristic opsin genetic construct in wild type beagle dogs","authors":"Samarendra Mohanty,&nbsp;Subrata Batabyal,&nbsp;Ananta Ayyagari,&nbsp;Najam A. Sharif","doi":"10.1002/jgm.3720","DOIUrl":"10.1002/jgm.3720","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A novel adeno-associated virus 2 (AAV2)-carried multi-characteristic opsin (MCO) (MCO-010) is undergoing several clinical trials as a novel therapeutic modality for the treatment of degenerative retinal diseases including retinitis pigmentosa and Stargardt disease. The present study aimed to determine the ocular and systemic safety of MCO-010 and the AAV2 vehicle in adult Beagle dogs following intravitreal (IVT) injection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The current safety/toxicology studies spanning 13 weeks described here utilized well-documented techniques to assess the effects of IVT injection of MCO-010 up to 2.2 × 10<sup>11</sup> genome copies (gc) per eye, or the AAV2 capsid (vehicle control) on gross behavioral and immunogenic changes, alterations in body weights, blood biochemistry, hematology, blood coagulation, gross necropsy lesions, organ weight changes and histopathology in the dogs (n = 4 per group; two males and two females per group). Immunohistochemical and functional electroretinogram studies were also conducted to determine MCO expression in the retina and determine any retinal toxicity associated with MCO-010.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were no significant deleterious effects of the MCO-010 (or the AAV2 at the tested doses) on any of the examined parameters, including the absence of any severe ocular or systemic adverse events. However, as expected, inflammation after IVT delivery of AAV2 and MCO-010 was observed in the conjunctivae of all groups of animals, although this self-resolved within 1 week post-injection. Quantitative immunohistochemical analyses of MCO-010-associated mCherry revealed successful delivery of the gene therapy within the inner retina.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, MCO-010 demonstrated a favorable safety profile when administered to the eyes of adult Beagle dogs of both sexes at dose levels up to 2.2 × 10<sup>11</sup> gc per eye, with no adverse effects observed. This dose was identified as the No Observed Adverse Effect Level (i.e. NOAEL) and guided selection of safe doses for human clinical trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":56122,"journal":{"name":"Journal of Gene Medicine","volume":"26 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Icariin attenuates asthmatic airway inflammation via modulating alveolar macrophage activation based on network pharmacology and in vivo experiments 基于网络药理学和体内实验,淫羊藿苷通过调节肺泡巨噬细胞活化减轻哮喘气道炎症。
IF 3.2 4区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pub Date : 2024-07-09 DOI: 10.1002/jgm.3718
Xiaofei Zhu, Bin Wang, Hang Yu, Congcong Li, Yuhang Zhao, Yuanyuan Zhong, Weifeng Tang, Yaolong Zhou, Xi Huang, Huahe Zhu, Yueren Wu, Kai Yang, Ying Wei, Zhen Gao, Jingcheng Dong

Background

Icariin (ICA) inhibits inflammatory response in various diseases, but the mechanism underlying ICA treating airway inflammation in asthma needs further understood. We aimed to predict and validate the potential targets of ICA against asthma-associated airway inflammation using network pharmacology and experiments.

Methods

The ovalbumin-induced asthma-associated airway inflammation mice model was established. The effects of ICA were evaluated by behavioral, airway hyperresponsiveness, lung pathological changes, inflammatory cell and cytokines counts. Next, the corresponding targets of ICA were mined via the SEA, CTD, HERB, PharmMapper, Symmap database and the literature. Pubmed-Gene and GeneCards databases were used to screen asthma and airway inflammation-related targets. The overlapping targets were used to build an interaction network, analyze gene ontology and enrich pathways. Subsequently, flow cytometry, quantitative real-time PCR and western blotting were employed for validation.

Results

ICA alleviated the airway inflammation of asthma; 402 targets of ICA, 5136 targets of asthma and 4531 targets of airway inflammation were screened; 216 overlapping targets were matched and predicted ICA possesses the potential to modulate asthmatic airway inflammation by macrophage activation/polarization. Additionally, ICA decreased M1 but elevated M2. Potential targets that were disrupted by asthma inflammation were restored by ICA treatment.

Conclusions

ICA alleviates airway inflammation in asthma by inhibiting the M1 polarization of alveolar macrophages, which is related to metabolic reprogramming. Jun, Jak2, Syk, Tnf, Aldh2, Aldh9a1, Nos1, Nos2 and Nos3 represent potential targets of therapeutic intervention. The present study enhances understanding of the anti-airway inflammation effects of ICA, especially in asthma.

背景:淫羊藿苷(ICA)可抑制多种疾病的炎症反应,但ICA治疗哮喘气道炎症的机制有待进一步了解。我们的目的是利用网络药理学和实验预测并验证淫羊藿苷治疗哮喘相关气道炎症的潜在靶点:方法:建立卵清蛋白诱导的哮喘相关气道炎症小鼠模型。方法:建立卵清蛋白诱导的哮喘相关气道炎症小鼠模型,通过行为学、气道高反应性、肺部病理变化、炎症细胞和细胞因子计数评估 ICA 的作用。然后,通过 SEA、CTD、HERB、PharmMapper、Symmap 数据库和文献挖掘 ICA 的相应靶点。Pubmed-Gene 和 GeneCards 数据库用于筛选哮喘和气道炎症相关靶点。重叠的靶点被用于构建相互作用网络、分析基因本体和丰富通路。随后,采用流式细胞术、实时定量 PCR 和 Western 印迹技术进行验证:结果:ICA可减轻哮喘的气道炎症;筛选出ICA的402个靶点、哮喘的5136个靶点和气道炎症的4531个靶点;216个重叠靶点被匹配并预测ICA具有通过巨噬细胞活化/极化来调节哮喘气道炎症的潜力。此外,ICA 降低了 M1,但升高了 M2。哮喘炎症破坏的潜在靶点在ICA治疗后得到恢复:ICA通过抑制肺泡巨噬细胞的M1极化缓解了哮喘的气道炎症,而M1极化与代谢重编程有关。Jun、Jak2、Syk、Tnf、Aldh2、Aldh9a1、Nos1、Nos2和Nos3是治疗干预的潜在靶点。本研究加深了人们对 ICA 抗气道炎症作用的了解,尤其是在哮喘中。
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引用次数: 0
期刊
Journal of Gene Medicine
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