基因治疗心肌缺血的载体应用新进展

近年来,随着基因治疗技术的不断进步,为心肌缺血的治疗开辟了一条全新的途径,并取得了一些令人鼓舞的进展。基因治疗主要包括治疗基因、基因转移载体以及基因导入途径三个方面。基因转移载体又在治疗基因和基因表达之间起着桥梁作用,因此,发展安全、高效的基因转移系统是基因治疗的关键之一。目前用于基因治疗心肌缺血基因转移的载体主要有病毒载体和非病毒载体。下面将就不同载体在心肌缺血的基因治疗中的应用进展进行简要的总结。     

基因治疗心肌缺血的载体应用新进展

近年来,随着基因治疗技术的不断进步,为心肌缺血的治疗开辟了一条全新的途径,并取得了一些令人鼓舞的进展。基因治疗主要包括治疗基因、基因转移载体以及基因导入途径三个方面。基因转移载体又在治疗基因和基因表达之间起着桥梁作用,因此,发展安全、高效的基因转移系统是基因治疗的关键之一。目前用于基因治疗心肌缺血基因转移的载体主要有病毒载体和非病毒载体。下面将就不同载体在心肌缺血的基因治疗中的应用进展进行简要的总结。     

罕见病基因治疗与孤儿药

孤儿药因面向的罕见病患者群小、市场需求低、研发成本高、缺乏政策支持等,其发展面临困境。随着精准医疗概念的提出,基 因治疗因能够从根本出发,给患者提供 “一劳永逸”的治疗,备受关注。基因治疗以单基因罕见病的治疗作为极佳切入点,为孤儿药的 研发带来了新的希望。概述基因治疗针对的疾病对象、实施策略和属性以及基因药物的结构及基因治疗的载体,以血友病的基因治疗为 例回顾罕见病基因治疗的发展,并分析罕见病基因治疗药物研发现状。     

An overview of gene therapy in head and neck cancer

Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction and expression, mediation of apoptosis and clinical response including pathological complete responses. The objective of this article is to provide an overview of the current available gene therapies for head and neck cancer.     

Gene therapy in cancer

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.     

Phoenix rising: gene therapy makes a comeback

Despite the first application of gene therapy in 1990, gene therapy has until recently failed to meet the huge expectations set forth by researchers, clinicians, and patients, thus dampening enthusiasm for an imminent cure for many life-threatening genetic diseases. Nonetheless, in recent years we have witnessed a strong comeback for gene therapy, with clinical successes in young and adult subjects suffering from inherited forms of blindness or from X-linked severe combined immunodeficiency disease. In this review, various gene therapy vectors progressing into clinical development and pivotal advances in gene therapy trials will be discussed.     

The emerging fields of suicide gene therapy and virotherapy

Gene therapy is defined as a technology aimed at modifying the genetic component of cells for therapeutic benefit. ‘Suicide genes’ can be introduced into cancer cells to make them more sensitive to chemotherapeutics or toxins. Chemotherapeutic suicide gene therapy approaches are known as gene-directed enzyme prodrug therapy or gene-prodrug activation therapy. Other approaches include replacement gene therapy, antisense strategies and induction of resistance to normal cells. All gene therapy strategies share a common component, which is the need for a selective delivery vehicle or vector with tumor-targeting capabilities. This need has led to the in-depth investigation of viruses as new vectors for gene therapy.     

Gene therapy. Therapeutic approaches and implications

The present article is an overview of gene therapy with an emphasis on different approaches and its implications in the clinic. Genetic interventions have been applied to the diagnosis of and therapy for an array of human diseases. The initial concept of gene therapy was focused on the treatment of genetic diseases. Subsequently, the field of gene therapy has been expanded, with a major focus on cancer. Although the results of early gene therapy-based clinical trials have been encouraging, there is a need for gene delivery vectors that feature reduced immunogenicity and improved targeting ability. The results of phases I/II clinical trials have suggested the important role of gene therapy as a versatile and powerful treatment tool, especially for human cancers. One reasonable expectation is that performing gene therapy at an earlier stage in the disease process or for minimal residual disease may be more advantageous.     

肿瘤基因治疗的研究进展

肿瘤是严重影响人类身体健康的重大疾病之一,肿瘤的发生发展是一个复杂的涉及到众多基因的过程,肿瘤的基因治疗也已经成为肿瘤治疗的研究热点之一。目前,肿瘤基因治疗的策略主要包括以下几个方面:基因沉默治疗、抑癌基因治疗、免疫基因治疗、自杀基因疗法、抑制肿瘤血管生成基因治疗、肿瘤多药耐药基因治疗、抗端粒酶疗法和多基因联合疗法等。我们简要地对上述策略及相关研究进展进行综述。     

基因治疗20年

1990年9月14日美国NIH临床中心首次采用基因治疗成功治愈腺苷脱氨酶（ADA）基因缺陷而患重度联合免疫缺损和免疫系统功能低下疾患,至今已整整20年,其发展迅速,从单纯的重组技术导入基因DNA发展到了涵盖DNA和RNA两个干预水平、和基因上调（如基因增补、矫正、置换等）及下调（基因失活）的两大策略,近年来的进展使得基因治疗登入《Science》杂志2009年度十大科学进展,我国在基因治疗领域诞生了第一个上市药物,有10多个制剂临床前和多个在临床研究。基因治疗在遗传病治疗中具备巨大潜力,已经成为当代生命科学中最有前景的研究方向之一。     

肿瘤基因治疗的研究进展

基因治疗作为一种新的治疗手段,给许多绝症患者带来希望。基因治疗的范围已从最初的单基因疾病扩展到恶性肿瘤、心脑血管及自身免疫等诸多领域,其中以恶性肿瘤为主要对象。本文综述了肿瘤基因治疗中的基因转移方法、基因治疗策略、导向基因治疗及其在应用上的问题与展望。     

Adenoviral gene therapy, radiation, and prostate cancer

Viral gene therapy has exceptional potential as a specifically tailored cancer treatment. However, enthusiasm for cancer gene therapy has varied over the years, partly owing to safety concerns after the death of a young volunteer in a clinical trial for a genetic disease. Since this singular tragedy, results from numerous clinical trials over the past 10 years have restored the excellent safety profile of adenoviral vectors. These vectors have been extensively studied in phase I and II trials as intraprostatically administered agents for patients with locally recurrent and high-risk local prostate cancer. Promising therapeutic responses have been reported in several studies with both oncolytic and suicide gene therapy strategies. The additional benefit of combining gene therapy with radiation therapy has also been realized; replicating adenoviruses inhibit DNA repair pathways, resulting in a synergistic sensitization to radiation. Other, nonreplicating suicide gene therapy strategies are also significantly enhanced with radiation. Combined radiation/gene therapy is currently being studied in phase I and II clinical trials and will likely be the first adenoviral gene therapy mechanism to become available to urologists in the clinic. Systemic gene therapy for metastatic disease is also a major goal of the field, and clinical trials are currently under way for hormone-resistant metastatic prostate cancer. Second- and third-generation "re-targeted" viral vectors, currently being developed in the laboratory, are likely to further improve these systemic trials.     

Targeted vectors for gene therapy of cancer and retroviral infections

Gene therapy has developed to a technology which rapidly moved from the laboratory bench to the bedside in the clinic. This implies safe, efficient and targeted gene transfer systems for suitable application to the patient. Beside the development of such gene transfer vectors of viral or nonviral origin, improvement of cell type specific and inducible gene expression is pivotal for successful gene therapy leading to targeted gene action. Numerous gene therapy approaches for treatment of cancer and retroviral infections utilize cell type specific and/or regulatable promoter and enhancer sequences for the selective expression of therapeutic genes in the desired cell populations and tissues. In this article the recent developments and the potential of expression targeting are reviewed for gene therapy approaches of cancer and retroviral infections.     

Taking the good out of the bad: lentiviral-based gene therapy of the hemoglobinopathies

Sickle cell disease and beta-thalassemia are excellent candidates for gene therapy since transfer of a single gene into hematopoietic stem cells should theoretically elicit a therapeutic response. Initial attempts at gene therapy of these hemoglobinopathies have proved unsuccessful due to limitations of available gene transfer vectors. With the extensive research on human immunodeficiency virus-1 due to the acquired immune deficiency syndrome pandemic, researchers have realized that this lentivirus, engineered to be devoid of any pathogenic elements, can be an effective gene transfer vector. This review discusses the gene therapy strategy for the hemoglobinopathies and outlines why lentiviral-derived vectors are particularly suited for this type of application, keeping past failures at gene therapy of these hemoglobinopathies in mind. Development, improvement, and methods for preparation of lentiviral-derived vectors are examined. Recently published results of successful gene therapy treatment of beta-thalassemic and sickle cell diseased mice using lentiviral-derived vectors are described. Finally, criticisms and future directions of lentiviral-based biotechnology are considered.     

Polymer based cardiovascular gene therapy

Therapeutic angiogenesis is a new potential treatment in cardiovascular disease. It is performed by the delivery of the angiogenic agents (protein, gene). Most important consideration for gene therapy is the construction of an effective therapeutic gene. Currently, VEGF is the most effective therapeutic gene for the neovascularization. We constructed the hypoxia-regulated VEGF plasmid using the Epo enhancer and RTP801 promoter. The efficiency of the pEpo-SV-VEGF and pRTP801-VEGF were evaluated by various methodsin vitro andin vivo. The results suggested that the hypoxia-inducible VEGF gene therapy system is effective and safe, which may be useful for the gene therapy of ischemic heart disease. Development of a safe and efficient gene carrier is another main requirement for successful gene therapy. Although viralbased gene delivery is currently the most effective way to transfer genes to cells, nonviral vectors are increasingly being considered forin vivo gene delivery. The advantages of nonviral gene therapy are lack of specific immunogenecity, simplicity of use, and ease of large-scale production. In addition, the simple conjugation of a targeting moiety to nonviral gene carrier can facilitate tissue-targeting gene delivery. We have developed two new gene carrier systems, TerplexDNA and WSLP (water soluble lipopolymer). These two are efficient carrier to ischemic myocardium and has low toxicity and high transfection efficiency. So it may allow for application ofin vivo gene therapy in the treatment of heart disease.     

Prostate cancer gene therapy-what have we learned and where are we going?

With recent advances in genetic engineering, tumor biology, and immunology, gene therapy has been recognized as a promising new treatment option for various cancers, including prostate cancer. Several clinical trials of prostate cancer gene therapy, using therapeutic genes which include suicide genes, immunomodulatory genes, tumor suppressor genes, and anti-oncogenes, are under way and preliminary reports have emerged. Although gene therapy for prostate cancer is still at an early stage and requires additional technological breakthroughs, new insights obtained from recent clinical trials indicate a promising potential for prostate cancer gene therapy. In this report, general concepts, current progress, and future prospects in prostate cancer gene therapy are summarized.     

当前肿瘤基因治疗中存在的主要问题及其解决途径

本文概述了当前肿瘤基因治疗研究中存在的一些主要问题,如绝大多数治疗方案中目的基因只有一个,肿瘤基因治疗缺乏靶向性,基因转移载体的效率、安全性及容量等问题。讨论了解决这些问题的主要途径,即肿瘤多基因联合治疗、直接体内途径基因治疗与靶向基因治疗、基因转移载体的改造。     

History of gene therapy

Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results.     

基因治疗的应用及研究进展

基因治疗是一种新的治疗手段,可用于癌症、遗传性疾病、感染性疾病、心血管疾病和自身免疫性疾病等的治疗。癌症基因治疗是基因治疗的主要应用领域。过去几年里,全球基因治疗临床试验取得了很大的进步,也遇到了很多困难。未来基因治疗的主要目标是发展安全和高效的基因导入系统,它们能将外源遗传物质靶向性地导入特异的细胞。简要综述了基因治疗研究和应用的进展、困难及其发展前景。     

基因治疗的发展现状、问题和展望

基因治疗是一种新的治疗手段,可以治疗多种疾病,包括癌症、遗传性疾病、感染性疾病、心血管疾病和自身免疫性疾病。癌症基因治疗是基因治疗的主要应用领域。过去几年里,全球基因治疗临床试验取得了很大的进步。实际上,基因治疗也遇到了很多困难。未来,基因治疗的主要目标是发展安全和高效的基因导入系统,它们能将外源遗传物质靶向性地导入到特异的细胞。本文主要综述基因治疗所取得的突出进展、所遇到的困难和发展前景。