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- Volume 15, Issue 2, 2015
Current Gene Therapy - Volume 15, Issue 2, 2015
Volume 15, Issue 2, 2015
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Targeting Angiogenic Genes as a Therapeutic Approach for Hepatocellular Carcinoma
Authors: Chi Hang Wong, Cesar S.C. Wong and Stephen L. ChanHepatocellular carcinoma (HCC) is a complex liver disease with limited treatment options and often resulting in a poor prognosis. The development of HCC depends on the formation of new blood vessels and it demonstrates hypervascularity and invasive property to the surrounding vasculature clinically. A complex network of growth factors acting on both tumor cells and endothelial cells mediates the angiogenesis in HCC. It is an attractive approach to inhibit the angiogenic processes as the treatment of HCC and therefore, anti-angiogenic TKIs were developed to inhibit the vessel formation in the tumors. However, it is currently perceived that the efficacy of these anti-angiogenic TKIs has reached plateau, and it is necessary to develop novel agents with non-TKI mechanism to inhibit the angiogenic targets. With the better understanding of molecular mechanisms that govern angiogenesis, as well as the advancement in biomedical engineering, new approaches of gene therapy have brought hopes for therapeutic intervention in HCC. Gene therapy is based on the transfer of genetic material to the patients with the aim to modify or correct the malignancy from its molecular basis. In this article, we will discuss the conventional anti-angiogenic therapies and the gene therapy approaches in HCC. The therapeutic potential of gene therapy for HCC treatment has been demonstrated and further development of anti-angiogenic may result in new treatment option for HCC patients.
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Aptamer-Mediated Cancer Gene Therapy
Authors: Dongxi Xiang, Sarah Shigdar, Greg Qiao, Shu-Feng Zhou, Yong Li, Ming Q. Wei, Liang Qiao, Hadi Al. Shamaileh, Yimin Zhu, Conglong Zheng, Chunwen Pu and Wei DuanCancer as a genetic disorder is one of the leading causes of death worldwide. Conventional anticancer options such as chemo- and/or radio-therapy have their own drawbacks and could not provide a cure in most cases at present. More effective therapeutic strategies with less side effects are urgently needed. Aptamers, also known as chemical antibodies, are single strand DNA or RNA molecules that can bind to their target molecules with high affinity and specificity. Such site-specific binding ability of aptamers facilitates the delivery and interaction of exogenous nucleic acids with diseased genes. Thus, aptamer-guided gene therapy has emerged as a promising anticancer strategy in addition to the classic treatment regimen. Aptamers can directly deliver anti-cancer nucleic acids, e.g. small interfering RNA, micro RNA, antimicroRNA and small hairpin RNA, to cancer cells or function as a targeting ligand to guide nanoparticles containing therapeutic nucleic acids. This review focuses on recent progress in aptamer-mediated gene therapy for the treatment of hepatocellular carcinoma and other types of cancers, shedding light on the potential of this novel approach of targeted cancer gene therapy.
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Current Status of Gene Therapy for Hepatocellular Carcinoma, with a Focus on Gene Delivery Approaches
Authors: Xiaoyu Wang, Zongguang Tai, Wei Zhang and Shen GaoHepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality rates, especially in East Asia. Gene therapy is a potential approach for treating HCC. An efficient and safe gene delivery method is a crucial factor for HCC gene therapy. In recent years, gene delivery systems, including viral and non-viral gene vectors, bacteria, and physical methods, have undergone substantial development. Among them, various non-viral vectors have been studied widely and in detail because they are relatively safe and have a high capacity. In this review, we focus on current and emerging HCC delivery techniques and address the challenges involved in the use and improvement of non-viral vectors.
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miR-122 is a Unique Molecule with Great Potential in Diagnosis, Prognosis of Liver Disease, and Therapy Both as miRNA Mimic and Antimir
Authors: Sharda Thakral and Kalpana GhoshalmiR-122, a completely conserved liver-specific miRNA in vertebrates, is essential for the maintenance of liver homeostasis. This 22 nucleotide RNA regulates diverse functions such as cholesterol, glucose and iron homeostasis, lipid metabolism and infection of hepatitis C virus (HCV) and of the parasitic protozoa, Leishmania donovani. It is the first miRNA that underwent successful clinical trials in HCV infected patients. In contrast, miR-122 expression is reduced in nonalcoholic steatohepatitis (NASH) patients, and in a subset of hepatocellular carcinoma (HCC) patients including hepatitis B virus (HBV) positive patients with highly invasive and metastatic cancer. Studies in mice genetically depleted of miR-122 have highlighted its critical role in liver biology. These mice progressively develop steatohepatitis, fibrosis and hepatocellular cancer, establishing it as a bona fide tumor suppressor. Additionally, delivery of miR-122 using a viral vector or liposomal nanoparticles resulted in liver tumor suppression in animal models. These results suggest miR-122 supplementation might be beneficial in NASH or HBV positive HCC patients. Furthermore, circulating miR-122 has emerged as a sensitive biomarker for liver injury. The ability of miR-122 to promote differentiation of embryonic and adult stem cells to hepatocyte-like cells in vitro suggests its potential role in driving the hepatic differentiation program. In this review, we will discuss the role of miR-122 in liver physiology and the deleterious consequences of its loss of function, its role as a sensitive biomarker for liver injury and therapeutic target. Development of novel technologies for targeted delivery of miR-122 to tumor cells and for direct monitoring of miR-122 in biological fluids is urgently needed for translating the basic research to the bedside. This review focuses on miR-122, the most abundant hepatic miRNA, in the context of liver health and diseases.
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Combined Therapy for Gastrointestinal Carcinomas: Exploiting Synergies Between Gene Therapy and Classical Chemo-Radiotherapy
Authors: Mariana Malvicini, Jorge B. Aquino and Guillermo MazzoliniSurgical resection is the only curative option for patients with gastrointestinal carcinomas. Unfortunately, the majority of patients are diagnosed in advanced stages when surgery is not possible. Moreover, the incidence and mortality for certain type of tumors such as hepatocellular carcinoma or pancreatic cancer are steadily increasing worldwide. In spite of the advances in the development of molecular targeted therapies for cancer, the impact on patient survival has been rather limited. It is unlikely that individual agents would be ultimately successful as monotherapy. There is a growing area of research focused on the combination of classical chemotherapy (e.g. cyclophosphamide, gemcitabine, paclitaxel and doxorubicin) with radiotherapy and/or gene therapy strategies. Combined approaches seem to be required due to multiple resistance mechanisms that tumors utilize to limit the activity of chemotherapeutic agents (e.g. the occurrence of multidrug resistance or epigenetic alterations), evade immune responses (e.g. induction of regulatory T cells or myeloid-derived suppressor cells) and to generate resistance against anti-angiogenesis or to radiotherapy by, for example, the induction of hypoxia-inducible factor 1. In addition, new studies suggest that combination of low dose of conventional chemotherapy and gene therapy could allow the development of synergic mechanisms able to achieve significant therapeutic effects against diverse tumors. Although cancer gene therapy is not yet available in clinical practice, advances being recently made look promising, especially when it was applied in combination with standard chemo- or radiotherapy protocols.
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Targeting Cancer Stem Cells as a Therapeutic Approach in Liver Cancer
Authors: Gang Zhou, George Wilson, Jacob George and Liang QiaoCancer stem cells (CSCs) are a subset of cells within tumours that have the ability to selfrenew, differentiate and resist both chemotherapy and radiotherapy. Evidence has emerged in recent years to support liver cancer stem cells (LCSCs) as the key tumour initiating cells and major drivers of tumour progression in hepatocellular carcinoma (HCC). Currently the major approaches to targeting LCSCs are ablating the expression of LCSC markers, disruption of key LCSCs signaling pathways, micro-RNA or siRNA targeting, inducing differentiation of LCSCs and the disruption of chemoresistance of LCSCs. However, complex crosstalk amongst gene regulatory pathways in LCSCs provides a major barrier in implementing these approaches in a clinical setting. Given these findings a deeper understanding of the pathways that mediate LCSC tumourigenesis is imperative for developing new therapeutic strategies for HCC and to improve clinical outcomes.
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Modulation of Notch Signaling as a Therapeutic Approach for Liver Cancer
Authors: Guang Wu, George Wilson, Jacob George and Liang QiaoNotch signaling is an evolutionarily conserved pathway crucial for the development and homeostasis of many organs including liver. Aberrant Notch signaling has been mechanistically linked to cancer development including liver cancer. The two principal types of liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC). HCCs comprise over 80% of all liver cancers and are the 6th most common malignancy worldwide. Hepatocellular carcinoma is also a cancer with an extremely poor prognosis, being the 3rd commonest cause of cancer-related mortality. Accumulating evidence indicates that the role of Notch signaling in liver cancer is more complex than once thought and is dependent on the expression of specific Notch signaling components and the complex crosstalk with other signaling pathways. Currently there are a variety of gene therapy based approaches used to target Notch signaling in preclinical studies to successfully treat liver cancer including neutralizing antibodies, siRNA, shRNA and miRNA. The use of targeted anti-Notch therapy in the clinic to treat liver cancer will require considerable refinement of our current knowledge on the regulation of Notch signaling components and their effects in both normal and malignant liver cells in order to target specific Notch subunits which are critical to liver cancer tumorigenesis but not to the homeostasis of normal cells. Using this approach will reduce the major side effects, which are frequently seen in patients treated with GSIs to inhibit the entire Notch signaling pathway. Here our understanding of Notch signaling is reviewed, highlighting its function in liver cancer initiation, progress and opportunities for liver cancer therapies.
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Exosomes: A Role for Naturally Occurring Nanovesicles in Cancer Growth, Diagnosis and Treatment
Authors: Akhil Srivastava, Justyna Filant, Katherine M. Moxley, Anil Sood, Scott McMeekin and Rajagopal RameshExosomes are 30 - 100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings.
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Apoptosis-Induction is A Novel Therapeutic Strategy for Gastrointestinal and Liver Cancers
Authors: Fei Wang, Haizhong Wang, Xiaotian Sun and Min LiGastrointestinal and liver cancers are among the most frequently encountered cancers worldwide. Though great strides have been made in improving the early detection and overall patient survival in the last decade, the currently available treatment approaches remain suboptimal due to drug resistance and side effects. Apoptosis is the most desirable type of programmed cell death in cancer therapy. By eliminating unnecessary and unwanted cells, apoptosis plays a critical role in development, physiology and homeostasis. Recent studies have shown that apoptosis-inducing therapy is a safe and effective anti-cancer approach, which thus may become one of the most important areas in cancer treatment. In this review, the authors provide an overview on the apoptosis system in multicellular organisms and summarize the recent advances of apoptosis-inducing therapeutic strategy for gastrointestinal and liver cancers.
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SiRNA Nanotherapeutics _The Panacea of Diseases?
Authors: Khan Farheen Badrealam, Swaleha Zubair and Mohammad OwaisRNAi based therapeutics hold s great promises to be an efficient strategy of the anti-gene realm in context of its therapeutic applications; however, despite significant potentials, its full efficacy cannot be realized in real sense owing to various confronts that plague its advancement. Efforts need to be driven for the development of specific and efficacious strategies to subdue some of their crucial constraints towards successes in clinics. This article will present the major impediments that encumber successful translation of siRNA concept into reality and the ongoing research endeavours to get through those stumbling blocks along with their inadequacies.
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Volumes & issues
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)
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New Hope for Intervertebral Disc Degeneration: Bone Marrow Mesenchymal Stem Cells and Exosomes Derived from Bone Marrow Mesenchymal Stem Cell Transplantation
Authors: Xiao-bo Zhang, Xiang-yi Chen, Jin Qi, Hai-yu Zhou, Xiao-bing Zhao, Yi-cun Hu, Rui-hao Zhang, De-chen Yu, Xi-dan Gao, Ke-ping Wang and Lin Ma
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