心血管疾病的基因治疗

基因治疗在先天遗传性以及后天获得性心血管疾病治疗中均具有广阔的发展前景. 对心血管疾病致病机理的深入认识和疾病基因组学研究的发展, 进一步促进了临床前基因治疗的研究进展. 但基因治疗过程中存在的机体细胞免疫反应、外源基因表达水平不足、在体基因转导效率低下等因素都成为基因治疗临床应用转化的瓶颈. 近年来, 基因导入载体和基因组编辑技术的发展为上述问题的改善和解决提供了新的思路. 目前成族规律间隔短回文重复序列(clustered regularly interspaced short palindromic repeats, CRISPR)/Cas9 基因组编辑技术已经成功应用于动物模型的在体基因编辑, 达到了显著改善血脂指标的疗效. 进一步研究体内组织特异和高效的基因导入方式, 提高基因编辑的靶向效率和特异性, 并建立全面有效的安全评估实验体系, 将推动基因治疗向临床应用的转化. 针对心血管疾病基因治疗中基因导入载体的研究以及CRISPR/Cas9 基因组编辑技术的应用展开讨论.     

帕金森病研究进展

 帕金森病（PD）是常见的神经系统变性疾病,典型的PD病理表现为脑中黑质多巴胺神经元退行性变和路易小体沉积,但这些改变不能完全解释PD产生的临床症状,目前PD的发病原因及机制尚不明确,尚未建立系统的早期诊断及保护治疗方式。随着诊断及治疗技术的提高,生物学标记物、脑网络及神经调控等有望为PD早期诊断、机制探索及个体化治疗提供基础。本文综述了PD在生物学标记物、脑网络研究及神经调控治疗领域的研究进展。     

卟啉MOFs材料应用于肿瘤治疗领域的研究进展

卟啉类化合物因其独特的物理和化学特性,在肿瘤治疗领域具有广阔的应用前景.但是卟啉类化合物存在水溶解性较差和易于自聚集等缺点,限制了其在肿瘤治疗上的广泛应用.而金属有机框架（MOFs）具有可调节孔径、可功能化修饰,以及生物相容性好等优点.因此,将卟啉作为有机连接体,结合金属簇构建卟啉MOFs材料,不仅可以克服卟啉类化合物固有的缺点,而且还能发挥MOFs的优异特性.文章综述了近年来卟啉MOFs材料的合成方法及其在肿瘤治疗方面的研究进展,同时探讨了其在肿瘤治疗领域的挑战.     

Silica nanoparticle is a possible safe carrier for gene therapy

In order to develop a safe and effective gene therapy carrier, some toxicological and biodynamical experiments were carried out on silica nanoparticles （SiNPs）. First we prepared SiNPs with appropriate portions of cyclohexane, deionized water and ethyl silicate, and then transfected the modified SiNPs and GFP plasmid DNA complex into the HT1080 cells to test the effectiveness of transfection for gene therapy. At the same time, we injected the SiNPs into a number of mice through tail vein. Then we made the mice crossed to evaluate the acute, long-term and reproductive toxicity. In vivo distribution analysis and pathological examination were made on both adult mice and their offspring. SiNPs were uniform and had an average diameter of 40 nm, and the modified SiNPs carried exogenous DNA molecules into target cells and the transferred GFP fusion gene was effectively expressed in the cells. The SiNPs injected via tail vein were widely distributed in almost all of tissues, and the injected mice had the ability to reproduce normally. The in vivo and in vitro results of this study clearly show that SiNPs can be used as a safe and effective carrier for gene transfection and gene therapy.     

新型Bola两亲分子作为基因治疗药物输递载体的研究

为检测新型Bola两亲分子(Orn-C16-G)用作基因载体的性能,制备了Bola与siRNA的复合物(Bolaplexes),用原子力显微镜观察其在不同复合比下的形貌;并转染Hela细胞,用CCK-8检测Bolaplexes的细胞毒性,用荧光显微镜、流式细胞仪表征Bolaplexes的细胞内吞效果。实验结果显示,复合比1∶1条件下,Bola分子可以有效地压缩siRNA分子形成较小尺寸的复合物(100～200 nm)。Bolaplexes可高效地进入Hela细胞,并且毒性低于商售转染试剂,有较好的应用前景。本研究为下一步Bola两亲分子用于基因治疗的临床研究奠定了基础。     

Investigation of hrDNA targeting vector-mediated tumor-specific suicide gene therapy for hepatocellular carcinoma

Vectors pose most pivotal problem of gene therapy[1]. Because of the high transfection efficiency both in vitro and in vivo, the viral vector has been employed in 70% clinical trials of gene therapy (http://www.wiley.co.uk/ genmed/clinical). However, thei…     

Recent progress in polymer-based gene delivery vectors

The gene delivery system is one of the three components of a gene medicine, which is the bottle neck of current gene therapy. Nonviral vectors offer advantages over the viral system of safety, ease of manufacturing, etc. As important nonviral vectors, polymer gene delivery systems have gained increasing attention and have begun to show increasing promising. In this review, the fundamental and recent progress of polymer-based gene delivery vectors is reviewed.     

Construction and anti-tumor effects of recombinant fowlpox virus expressing Newcastle disease virus hemagglutinin-neuramidinase gene

Hemagglutinin-neuramidinase (HN), a Newcastle disease virus-derived protein, not only mediates receptor recognition but also possesses neuraminidase (NA) activity, the ability to cleave a component of those receptors, N-acetylneuraminic acid (NAcneu, sialic acid). It is known that this protein in mammalian species, including human beings, has interesting anti-neoplastic as well as immune stimulating properties. To explore the use of the HN gene in cancer gene therapy, we constructed a recombi-nant fowlpox virus expressing the HN protein (vFV-HN) and compared the anti-tumor activity of the recombinant virus with that of wild-type fowlpox virus (FPV) in vivo and in vitro. Here we found that although B16 cells were somewhat resistant to the basal cytotoxic effect of wild-type fowlpox virus, infection with vFV-HN caused a pronounced cytotoxic effect and, the survival of tumor-bearing mice immunized with vFV-HN was significantly increased compared with the survival of mice immunized with the FPV alone. Furthermore, the immunization of mice with vFV-HN elicited a B16 tumor-specific cytotoxic T lymphocyte (CTL) response and clonal expansion of both CD4 and CD8 T cell populations in vivo. In addition, T cells from lymph nodes of mice vaccinated with vFV-HN secreted high levels of the Th1 cytokine IL-2 and IFN-γ, indicating that the regression of tumor cells is related to a Th1-type dominant immune response. These results demonstrate that vaccination with vFV-HN may be a potential strategy for cancer gene therapy.     

Cx32 gene mutation associated with X-linked recessive Charcot-Marie-Tooth disease

The form of Charcot-Marie-Tooth (CMT) neuropathy that maps to Xql3 is X-linked dominant, or X-linked intermediate. Heterozygous females are more mildly affected than hemizygous males. It has been known that this type of CMT is caused by mutations of connexin32 (Cx32) gene. A typical X-linked recessive Charcot-Marie-Tooth Chinese family was analyzed with single strand conformation polymorphism method. A Cx32 gene point mutation, ArglSGln, in exon 2 was identified in all affected family members, suggesting that this mutation is responsible for the CMT incidence of this family.     

铜基纳米材料在增强化学动力学治疗上的应用研究

和传统治疗相比,化学动力学治疗(CDT)被认为是一种低副作用且无创的治疗方法,在众多的治疗方法中脱颖而出.CDT通过金属离子介导的芬顿反应或类芬顿反应,将肿瘤中过表达的过氧化氢(H2O2)分解为剧毒的羟基自由基(·OH),从而杀死肿瘤细胞.近年来,铜基纳米材料在CDT中蓬勃发展,极大地提高了CDT的效率.因此,基于铜基...     

慢病毒载体及其介导的RNA干扰在基因治疗中的应用研究

主要就慢病毒载体及其介导的RNA干扰技术在基因治疗中的应用研究进行了综述,并对其在该领域具有的广阔前景进行了展望.慢病毒载体作为一种新型的载体,可有效地将携带的目的基因导入宿主细胞,并将其整合到宿主细胞基因组中,从而使目的基因得以持久稳定地表达.该载体因具有高感染性、高表达效率及不易诱发宿主免疫反应等优点,已成为基因治疗研究中的一个重要工具.RNA干扰技术可以特异性抑制或关闭特定基因的表达,因此该技术可广泛应用在基因功能探究和恶性肿瘤治疗等领域.由慢病毒载体介导的RNA干扰技术能持久、稳定、特异性地抑制各类细胞中特定基因的表达,在病毒感染、肿瘤等疾病的基因治疗中被广泛应用,成为生物医学领域的新热点.     

TNF基因治疗肿瘤的研究进展

肿瘤坏死因子 (TNF)是一种既能直接杀死肿瘤细胞 ,又能通过激活免疫系统发挥抗肿瘤作用的细胞因子 .其基因工程药品临床应用后 ,具有严重的毒副作用 ,因此 ,人们开始了TNF基因冶疗的研究 .TNF基因治疗为TNF在肿瘤治疗中的应用开拓了新的途径     

Progress in non-viral gene delivery systems fabricated via supramolecular assembly

Gene delivery systems are one of key issues that limit the development of gene therapy. The novel non-viral gene delivery systems fabricated via supramolecular assembly have begun to show increasing promising and applications in gene therapy due to its suitable nanometric size,controllable structure and excellent biocompatibility. In this review, the fundamental and recent progress of non-viral gene supramolecular assembly is reviewed. Artificial viruses the future direction of non-viral gene delivery systems are also described.     

基于化学动力学疗法的联合治疗在肿瘤中的研究进展

由于肿瘤微环境(TME)的复杂性,单一的治疗策略难以有效地消除肿瘤,因此需要多种方法以克服单一治疗策略的缺陷.化学动力学疗法(CDT)是一种新兴的癌症治疗策略,通过芬顿或类芬顿反应,将内源性过氧化氢(H₂O₂)转化为羟基自由基(·OH)杀死癌细胞.该治疗方法因其侵袭性小、肿瘤特异性高而受到广泛研究.但是,温和的酸性pH值、低H₂O₂含量,以及TME中过表达的还原物质严重抑制了CDT效率.因此,基于CDT的联合治疗策略得到了广泛的发展.文章对近年来CDT联合治疗策略进行了概述,并对其进行了展望.     

四例血友病B患者基因治疗的临床试验

报道了对四例血友病Ｂ患者基因治疗的临床试验，取自四例血友病Ｂ患者的自体皮肤成纤维细胞，通过反转录病毒介导的基因转移，能高效地分泌人凝血因子Ⅸ。用胶原包埋经遗传修饰的自体皮肤成纤维细胞，再移植到血友病Ｂ患者皮下。四例患者经治疗后，自发出血症状得到了减轻，血浆中凝血因子Ⅸ蛋白浓度和凝血活性明显地增加，其中两例患者增加较大，达到正常值的４％￣５％。另外两例患者体内的凝血因子Ⅸ和凝血活性也有不同程度的提高     

声动力疗法的研究进展

声动力疗法(SDT)是通过超声和声敏剂的协同作用,并利用多种机制共同作用达到杀死癌细胞的目的 .超声的机械波穿透力强,SDT利用超声激活声敏剂产生局部毒性,与传统治疗方法相比,对正常细胞和组织伤害较小,是一种新型的治疗癌症的方法 .声敏剂是影响SDT的重要因素,单一有机声敏剂有一定的生物应用缺陷,现在主要的研究方向是将声敏剂和纳米技术相结合,使用纳米载体负载有机声敏剂和新型无机声敏剂.目前为止,SDT仍处于临床前和临床研究阶段,大量体外和体内实验表明:SDT对于多种癌细胞有杀伤作用,具有广阔的应用前景.简述了SDT作用机制、声敏剂的种类和当前应用研究的进展.     

线粒体病的基因治疗

线粒体基因突变导致的线粒体病仍是不治之症,目前只有针对症状的支持性疗法.根治线粒体病只能寄希望于基因治疗.基因治疗的主要目标是修补特定基因突变导致的功能缺陷,或促使异质性的转变,以降低突变型与野生型基因组的比例.所探讨的途径主要包括:①在肽核酸和锌指肽的引导下选择性抑制突变基因组的复制;②利用特定的限制性内切酶去除突变...     

帕金森病的认知障碍

 帕金森病是仅次于老年痴呆的第二大神经退行性疾病。随着社会老龄化的加剧,帕金森病的患病率大幅提高。认知障碍等非运动症状是目前影响帕金森病患者生活质量的主要因素。帕金森病认知障碍的生物学机制目前尚不明确,临床上患病率高、识别率低,缺乏有效的治疗手段。本文将围绕帕金森病认知障碍的前沿热点问题,介绍相关神经科学和医学研究的最新进展,涵盖认知障碍的神经化学基础、风险基因、其他非运动症状的影响和生物标记物等。     

使用病毒载体的罕见病基因疗法临床进展

 很大一部分的罕见病由遗传因素决定,难以用普通的小分子或大分子药物治愈,而基因治疗有望从根本上修正人体功能的缺失或异常,给罕见病患者带来改善生活质量的希望。目前许多基因疗法的临床试验正在开展,病毒载体是常用的基因递送方法,本文讨论了用于临床基因递送的多种病毒载体,包括腺相关病毒、逆转录病毒和慢病毒,重点列举了这些病毒在罕见病临床试验中的研究、应用和进展,评价了这些病毒的优缺点,并简述了基因疗法的研究方向及应用前景。