腺相关病毒载体介导的肿瘤基因治疗研究进展

基因治疗有望成为肿瘤治疗的有效手段,用于携带外源基因的载体在肿瘤基因治疗中发挥了重要作用.其中腺相关病毒(AAV)载体具有安全性高、长效表达、宿主范围广泛等优点,在基因治疗中得到越来越广泛的应用.本文重点综述AAV的生物特点、载体发展及其在肿瘤基因治疗中的应用.     

腺相关病毒载体与基因治疗的研究进展

腺相关病毒(AAV)是基因治疗中最有希望的载体之一,它具有非致病性、对宿主免疫原性弱及广泛的细胞和组织亲嗜性等优点.本文着重探讨了AAV的血清分型与高滴度表达抑制转录因子的重组AAV的制备,并综述了AAV在基因治疗糖尿病及心血管病中的最新研究进展.     

病毒载体基因治疗药品的临床设计与评价思考

基因治疗是将外源性遗传物质通过多种方法转移到靶细胞中,用来治疗特定疾病。基因治疗已逐渐成为药品开发和风险投资领域的热点,或将成为未来治疗人类疾病的重要手段。然而,以病毒为载体的基因治疗相比传统药物开发存在诸多差异性。因此,本文将从病毒载体基因治疗产品的基本概念出发,结合美国食品药品监督管理局(FDA)的系列指南,通过对美国FDA批准上市的腺相关病毒载体的治疗药物Zolgensma,慢病毒载体的治疗药物Kymriah,逆转录病毒载体的治疗药物Yescarta,以及溶瘤病毒药物Imlygic的临床审评案例分析,从受试者选择,对照组与盲法,剂量与疗程,治疗方案,医学监查与随访多个维度对临床研究的设计和评价进行研究。研究结果提示以病毒载体为代表的基因治疗产品的临床试验设计需要着重考虑适合基因治疗的受试者群体、个体化的剂量选择模式、风险最小化的给药方案、以及根据不同载体特点确定的医学监察策略和长期随访时间等,以满足充分评价的需要。     

非病毒载体在肿瘤基因治疗领域的研究进展

随着肿瘤基因治疗领域的研究进展，临床应用逐渐增多。载体是癌症基因治疗的主要难题。当前广泛使用的病毒载体存在的安全问题越来越受到人们的重视，已经有多种非病毒载体用于肿瘤基因治疔，如：裸DNA直接注射、阳离子脂质、阳离子聚合物。研究非病毒载体的目标是：它能像靶向的合成病毒载体那样对肿瘤组织表现出高度特异性；具有很高的转染效率；潜在的安全性问题能够被控制。     

基因治疗载体的研究进展

参考国内外相关文献，综合介绍逆转录病毒载体、腺病毒载体、痘苗病毒载体、单纯疱疹病毒载体、腺病毒相关病毒载体、艾滋病病毒(HIV)载体和脂质体载体以及氧化铁磁性纳米颗粒等基因治疗载体的研究进展。     

基因治疗的载体系统及应用

目前的基因载体系统可分为病毒载体和非病毒载体。利用病毒载体介导的基因转移 ,以其高转染率和良好靶向性成为肿瘤基因治疗中应用最广泛的方法。非病毒载体由于其非免疫性和易于生产性而逐渐引起学者瞩目。基因治疗是一种用正常基因取代缺陷基因的治疗 ,目前主要用于肿瘤治疗 ,同时在基因治疗造血细胞疾病、心血管疾病、风湿性关节炎方面 ,已在动物试验中取得一定进展。1　基因载体系统本文介绍几种将外源基因引入宿主细胞的转移方法 ,这些方法可使外源基因短期 (数天 )或长期 (数星期或数年 )稳定的表达[1] 。通常可将这些方法分为病毒载…     

基因治疗用腺病毒载体

腺病毒载体转基因效率高,不受靶细胞是否为分裂细胞所限;容易制得高滴度病毒载体;生物活性评价较简便;在临床基因治疗方面有了越来越多的应用.但由于较高的免疫原性,导致一过性表达及静脉反复使用困难.     

基因治疗用腺病毒载体

腺病毒载体转基因效率高,不受靶细胞是否为分裂细胞所限;容易制得高滴度病毒载体;生物活性评价较简便;在临床基因治疗方面有了越来越多的应用.但由于较高的免疫原性,导致一过性表达及静脉反复使用困难.     

重组腺相关病毒载体在肺癌治疗中的应用

重组腺相关病毒（recombination Adeno-associated virus,rAAV）突出的特点使其成为基因治疗载体中的佼佼者,本文综述了rAAV基因药物在肺癌治疗中取得的进展并对其未来发展趋势进行了探讨。     

Dose-response and control in viral vectors based preclinical and clinical therapy

The objective for human gene therapy is to express exogenous DNA at the targeting cells or nearby to produce a practical and efficient therapeutic dosage at an appropriate time （quantitative pharmacology） with a safe manner.However, the use of genetic material as therapeutic agents has produced many novel and challenging obstacles that remain to be overcome. The obstacles include the formulation or packaging of the DNA, elements and construct of in vivo delivery system, penetration of biological barriers, DNA elimination within the cell and from the tissue compartments of the whole body, control of product expression and overt toxicity. Furthermore, the dose response and control of viral vectors can also be affected by viral serotypes, tissue tropisms, cell targeting, drug regulation, injection route, age and sex, etc. This review discusses the quantitative pharmacological control and effect of current viral vector based preclinical and clinical therapy.[第一段]     

基因治疗药物递送系统研究进展

基因治疗在癌症及许多遗传性疾病治疗方面有着重要意义。由于基因药物在体内很容易降解,为了有效地将基因药物递送至靶组织、靶细胞及靶细胞器发挥作用,开发安全高效的基因药物载体体系是十分必要的。随着基因治疗的发展和进一步完善,各类非病毒和病毒载体材料应运而生。针对各类基于非病毒和病毒载体的基因递送系统研究及其临床试验中的进展进行汇总。

     

The potential of adeno-associated viral vectors for gene delivery to muscle tissue

Introduction: Muscle-directed gene therapy is rapidly gaining attention primarily because muscle is an easily accessible target tissue and is also associated with various severe genetic disorders. Localized and systemic delivery of recombinant adeno-associated virus (rAAV) vectors of several serotypes results in very efficient transduction of skeletal and cardiac muscles, which has been achieved in both small and large animals, as well as in humans. Muscle is the target tissue in gene therapy for many muscular dystrophy diseases, and may also be exploited as a biofactory to produce secretory factors for systemic disorders. Current limitations of using rAAVs for muscle gene transfer include vector size restriction, potential safety concerns such as off-target toxicity and the immunological barrier composing of pre-existing neutralizing antibodies and CD8⁺ T-cell response against AAV capsid in humans.

Areas covered: In this article, we will discuss basic AAV vector biology and its application in muscle-directed gene delivery, as well as potential strategies to overcome the aforementioned limitations of rAAV for further clinical application.

Expert opinion: Delivering therapeutic genes to large muscle mass in humans is arguably the most urgent unmet demand in treating diseases affecting muscle tissues throughout the whole body. Muscle-directed, rAAV-mediated gene transfer for expressing antibodies is a promising strategy to combat deadly infectious diseases. Developing strategies to circumvent the immune response following rAAV administration in humans will facilitate clinical application.     

经修饰的聚阳离子载体在基因治疗中的应用进展

合成的多聚物载体作为癌细胞靶向治疗的载体在基因治疗中发展迅猛,拥有广阔的研究前景。随着人类基因组测序工作的完成,基因靶序列的不断更新,基因病的存在促使人们发明一种以基因为基础的治疗方案。以往所采取的非病毒载体治疗手段存在着转染效率低、表达含量低等缺陷。在众多合成的多聚物载体中,聚烯酰亚胺、聚酰胺-胺型树状高分子材料在基因治疗中应用广泛。本文综述了以聚乙烯亚胺、聚酰胺-胺型树状高分子材料作为基本结构进行修饰的基因载体的研究进展,并讨论了该领域未来可能的发展方向。     

Novel lentiviral vectors for human gene therapy

This review summarises an emerging viral vector system for use in human gene therapy - lentiviral vectors. Lentiviral vectors have several advantages over existing viral vectors. They can stably express transgenes in non-dividing cells in vivo without provoking a significant immune response. They can be produced to a high titre and can be pseudotyped with heterologous envelope proteins to confer broad tropism. Although not without safety concerns, the properties of lentiviral vectors makes them an attractive choice for human gene therapy.     

Polymers for viral gene delivery

Background: The development of viral vectors capable of providing efficient gene transfer in diseased tissues without causing any pathogenic effects is pivotal for overcoming the many challenges facing gene therapy. Objective: Immune responses against viral vectors, inadequate gene expression and inefficient targeting to specific cells in vivo are some of the major problems limiting the clinical utility of viral gene therapy. Methods: This review will focus on recent progress in strategic polymer-based modifications to improve the performance and biocompatibility of a variety of viral vectors. We will discuss the preclinical development of four approaches involving injectable polymers, polyelectrolytes, polymer microspheres and polymer–virus conjugates. Results/conclusion: Much progress has been made in creating ‘hybrid’ gene delivery vectors that combine the strengths of polymers and viruses. With further optimization, these hybrid vectors, which may be safer and more effective, are likely to succeed in clinical applications.     

Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®)

There has been great interest over the past two decades in developing gene therapies (GTs) to treat a variety of diseases; however, translating research findings into clinical treatments have proved to be a challenge. A major milestone in the development of GT has been achieved with the approval of alipogene tiparvovec (Glybera^®) in Europe for the treatment of familial lipoprotein lipase deficiency. At this important stage with the evolution of GT into the clinic, this review will examine the safety aspects GT with adeno-associated virus (AAV) vectors. The topics that will be covered include acute reactions, immunological reactions to the AAV capsid and expressed transgene, viral biodistribution and shedding, DNA integration and carcinogenicity. These safety aspects of GT will be discussed with a focus on alipogene tiparvovec, in addition to other AAV vector GT products currently in clinical development.     

年龄相关性黄斑变性基因治疗的药理与临床研究进展

年龄相关性黄斑变性（AMD）是由多因素共同诱发的视网膜黄斑区改变,基因治疗可以显著改善AMD患者临床症状,减轻长期玻璃体内治疗相关的治疗负担,提高临床适应性。尽管已取得多项成果,但基因疗法仍处于起步阶段,多数药物的临床试验仍处于研究阶段。通过整理近10年以来AMD的相关靶点治疗产品的药理研究与临床研究进展,并根据不同靶点或新载体进行分类,结合已取得的临床试验结果,评估基因治疗AMD的可行性与安全性,以期对于AMD相关靶点、治疗技术创新与载体开发提供参考。     

Gelatin-based delivery systems for cancer gene therapy

Gelatin is a natural, biocompatible, nontoxic, edible, and inexpensive macromolecule. These properties result in its wide application in pharmaceutical, medical, and cosmetic products. Recently, it has been used for the delivery of such gene therapeutic entities as plasmid DNA. This review discusses the in vivo and in vitro studies using gelatin for delivery of therapeutic genes to cancerous cells. Recent studies show that present cancer gene therapy using gelatin is lacking in both efficiency and specificity in comparison with viral vectors, whereas complexes of therapeutic DNA with modified gelatin possibly offer a safe and efficient strategy for systemic administration of therapeutic genes to solid tumors compared to injection of naked plasmid DNA. The future of these promising approaches lies in the development of better techniques for preparing gelatin–gene complexes with the aim of a gelatin-based cancer gene therapy with comparable efficiency to viral vectors but with the added advantage of biosafety for patients.