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1.
基因治疗为许多无法用小分子药物治疗或小分子药物长期疗效不佳的神经系统疾病提供了希望。但血脑屏障的存在却使外源性基因难以进入脑内,是中枢神经系统转基因治疗的主要障碍。从最初人为地开放血脑屏障,到现在利用分子生物学方法开发出高效的新型非病毒载体,探索经血管途径转基因治疗和增强目的基因的靶向性已成为中枢神经系统疾病转基因治疗研究的热点。 相似文献
2.
载药纳米粒在治疗中枢神经系统疾病中的应用前景 总被引:1,自引:0,他引:1
血脑屏障的存在不利于中枢神经系统疾病的治疗。载药纳米粒是一种新型药物输送载体。以纳米粒为载体 ,药物或核苷酸片断可跨越血脑屏障靶向脑组织。文章综述了载药纳米粒与血脑屏障的相互作用机制 ,以及纳米粒作为药物和基因载体用于中枢神经系统疾病治疗的研究进展。 相似文献
3.
血脑屏障的存在不利于中枢神经系统疾病的治疗。载药纳米粒是一种新型药物输送载体。以纳米粒为载体,药物或核苷酸片断可跨越血脑屏障靶向脑组织。文章综述了载药纳米粒与血脑屏障的相互作用机制,以及纳米粒作为药物和基因载体用于中枢神经系统疾病治疗的研究进展。 相似文献
4.
许金明 《国际脑血管病杂志》1998,(1)
血脑屏障对大分子肽类药物的通透性直接关系到中枢神经系统疾病的药物治疗效果。对血脑屏障的药物转运机制、影响大分子肽类药物血脑屏障通透性的因素以及大分子肽类药物血脑屏障通透性的可能途径及其临床意义的研究,是提高大分子肽类药物疗效,降低治疗成本的重要课题。 相似文献
5.
血脑屏障与药物转运 总被引:1,自引:0,他引:1
吴俊芳 《国际脑血管病杂志》1994,(3)
血脑屏障的药物转运直接关系到脑血管病的药物治疗。文章对血脑屏障的解剖生理基础,药物及肽类转运的机制以及增加中枢神经系统药物的途径等方面进行了综述。 相似文献
6.
载脂蛋白E(APOE基因,apoE蛋白)除了在脂类代谢中的作用,近年研究聚焦于其在中枢神经系统疾病中的重要作用。由于apoE全蛋白分子量大,不能透过血脑屏障,体外合成来自受体结合域的拟apoE肽备受关注。本文对中枢神经系统疾病中拟apoE肽的研究进展进行综述。 相似文献
7.
P-糖蛋白是ATP结合盒转运超家族成员之一,在体内许多部位均有表达,与多药耐药性有关。作为一种外排泵,血脑屏障内的P-糖蛋白能排出内源性底物和外源性化学物质以保持脑内环境的稳定,但同时也限制了治疗性药物在脑内的浓度,从而使治疗效果减弱。P-糖蛋白抑制剂可促进药物通过血脑屏障,对提高脑内药物的浓度和中枢神经系统药物的生物利用度具有重要意义。 相似文献
8.
中枢神经系统(CNS)疾病,如阿尔兹海默病,帕金森病,艾滋痴呆,脑膜炎已经成为威胁人类健康的严重疾病,这些疾病致使患者的生活质量下降,且给社会和家庭增添了巨大的负担.而用于治疗这类疾病的药物,由于人体中血脑屏障(BBB)的存在,无法到达患病部位或到达后有效浓度不足导致治疗效果不佳.据报告,美国食品与药物管理局2006~ 2009年间批准上市的74种新药中,仅有小部分新药是针对老年痴呆症、帕金森氏病、亨廷顿舞蹈病等CNS疾病的,且取得的疗效并不理想.药物无法有效通过BBB是CNS疾病新药开发的主要制约因素,如何使药物透过BBB或增大透过率成为人们治疗CNS疾病所面临的一道难题. 相似文献
9.
10.
肝脏基因治疗的范围包括遗传性肝脏疾病、后天获得性肝脏疾病以及肝外疾病等三个方面。本文就肝脏转基因治疗的研究现状和前景进行了讨论。 基本原理 根据载体不同,肝脏转基因可分为病毒转基因和DNA转基因两大类。前者先构建重组病毒颗粒,然后用重组病毒颗粒感染肝细胞。重组病毒颗粒带有治疗基因,但缺乏编码病毒功能的基因,不能在肝细胞中复制。最 相似文献
11.
Permeation of growth hormone across the blood-brain barrier 总被引:1,自引:0,他引:1
Exogenous GH can affect central nervous system function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the blood-brain barrier (BBB) by a specific transport system and found that both mice and rats have small but significant uptake of GH into the brain without a species difference. Determined by multiple-time regression analysis, the blood-to-brain influx transfer constants of 125I-labeled rat GH in mice (0.23+/-0.07 microl/g.min) and rats (0.32+/-0.04 microl/g.min) were comparable to those of some cytokines of similar size, with a half-time disappearance of 125I-GH of 3.8-7.6 min in blood. Intact 125I-GH was present in both serum and brain homogenate 20 min after iv injection. At this time, about 26.8% of GH in brain entered the parenchyma, whereas 10% was entrapped in endothelial cells. Neither excess GH nor insulin showed acute modulation of the influx, indicating lack of a saturable transport system for GH at the BBB. Binding and cellular uptake studies in cultured cerebral microvessel endothelial cells (RBE4) further ruled out the presence of high-capacity adsorptive endocytosis. The brain influx of GH by simple diffusion adds definitive value to the long-disputed question of whether and how GH crosses the BBB. The central nervous system effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system. 相似文献
12.
Noninvasive gene targeting to the brain 总被引:22,自引:0,他引:22
Shi N Pardridge WM 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(13):7567-7572
Gene therapy of the brain is hindered by the presence of the blood-brain barrier (BBB), which prevents the brain uptake of bloodborne gene formulations. Exogenous genes have been expressed in the brain after invasive routes of administration, such as craniotomy or intracarotid arterial infusion of noxious agents causing BBB disruption. The present studies describe the expression of an exogenous gene in brain after noninvasive i.v. administration of a 6- to 7-kb expression plasmid encoding either luciferase or beta-galactosidase packaged in the interior of neutral pegylated immunoliposomes. The latter are conjugated with the OX26 mAb to the rat transferrin receptor, which enables targeting of the plasmid DNA to the brain via the endogenous BBB transferrin receptor. Unlike cationic liposomes, this neutral liposome formulation is stable in blood and does not result in selective entrapment in the lung. Luciferase gene expression in the brain peaks at 48 h after a single i.v. administration of 10 microg of plasmid DNA per adult rat, a dose that is 30- to 100-fold lower than that used for gene expression in rodents with cationic liposomes. beta-Galactosidase histochemistry demonstrated gene expression throughout the central nervous system, including neurons, choroid plexus epithelium, and the brain microvasculature. In conclusion, widespread gene expression in the brain can be achieved by using a formulation that does not employ viruses or cationic liposomes, but instead uses endogenous receptor-mediated transport pathways at the BBB. 相似文献
13.
Efficient transduction of neural cells in vitro and in vivo by a baculovirus-derived vector 总被引:26,自引:0,他引:26
Sarkis C Serguera C Petres S Buchet D Ridet JL Edelman L Mallet J 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(26):14638-14643
Gene delivery to the central nervous system is central to the development of gene therapy for neurological diseases. We developed a baculovirus-derived vector, the Bac-CMV-GFP vector, containing a reporter gene encoding for the green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) promoter. Two neuroblastomal cell lines and three human primary neural cultures could be efficiently transduced. In all cases, addition of butyrate, an inhibitor of histone deacetylase, increased the level of expression in terms of the number of GFP-expressing cells and the intensity of fluorescence. The level of expression in a human telencephalic culture was over 50% of transduced cells with a multiplicity of infection of 25. GFP expression was demonstrated to be genuine expression and not pseudotransduction of the reporter protein. Most interestingly, Bac-CMV-GFP could transduce neural cells in vivo when directly injected into the brain of rodents and was not inactivated by the complement system. Thus, baculovirus is a promising tool for gene transfer into the central nervous system both for studies of the function of foreign genes and the development of gene therapy strategies. 相似文献
14.
The integrity of the blood-brain barrier (BBB) is an important aspect of normal central nervous system (CNS) function. Recently, it was shown that the BBB breakdown is one of the predisposing factors in the pathogenesis of thiamine-deficiency encephalopathy. The result is discussed along with some reviews on previous research of BBB integrity in thiamine deficiency. 相似文献
15.
Roscoe O. Brady Chunzhang Yang Zhengping Zhuang 《Journal of inherited metabolic disease》2013,36(3):451-454
The extraordinary benefit of enzyme replacement therapy (ERT) on the systemic manifestations of Gaucher disease was demonstrated in 1991. Since that time, investigators have devoted substantial effort to improve the delivery of enzymes to the brain because many hereditary metabolic disorders are characterized by extensive central nervous system involvement. Because the required supplemental enzyme is too large to cross the blood-brain barrier (BBB), ERT for central nervous system involvement was out of the question at that time. Several innovative strategies that have been reported to overcome this impediment are discussed. Recent investigations have provided additional insight concerning the pathogenesis of enzyme deficiency disorders. For many years it was presumed that alterations of the amino acid sequence of enzymes such as glucocerebrosidase reduced the catalytic activity of the enzyme. It has recently been shown that the decrease of glucocerebrosidase activity was the result of a quantitative loss of the amount of this enzyme. Significant increases of its activity were obtained with small molecule inhibitors of histone deacetylase that cross the BBB. The effect of such materials on neuronopathic Gaucher disease and other CNS metabolic disorders is discussed. 相似文献
16.
Gene transfer is a powerful, evolving technique that uses a biologic vehicle (eg, an engineered adenovirus) to introduce a specific gene of interest (ie, a recombinant gene) into a target tissue. This approach, which has considerable therapeutic potential, underlies the concept
of gene therapy. Several studies have characterized the morphologic, biochemical, and functional effects of recombinant gene
expression in animal and human cerebral arteries, and support the possibility of gene therapy for cerebrovascular disease.
However, for successful integration into future clinical practice, key issues concerning vector safety, delivery methods,
and transduction specificity need to be addressed. Alongside completion of the Human Genome Project, transfer of novel genes
into the central nervous system is likely to impact greatly on our ability to favorably modify diseased human tissue. Knowledge
of the fundamental concepts of cerebrovascular gene transfer is therefore useful to understanding both its molecular basis
and potential clinical utility. 相似文献
17.
The neuroprotective agent SR 57746A abrogates experimental autoimmune encephalomyelitis and impairs associated blood-brain barrier disruption: implications for multiple sclerosis treatment.
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B Bourrié E Bribes M Esclangon L Garcia J Marchand C Thomas J P Maffrand P Casellas 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(22):12855-12859
Experimental autoimmune encephalomyelitis (EAE) is a T cell autoimmune disorder that is a widely used animal model for multiple sclerosis (MS) and, as in MS, clinical signs of EAE are associated with blood-brain barrier (BBB) disruption. SR 57746A, a nonpeptide drug without classical immunosuppressive properties, efficiently protected the BBB and impaired intrathecal IgG synthesis (two conventional markers of MS exacerbation) and consequently suppressed EAE clinical signs. This compound inhibited EAE-induced spinal cord mononuclear cell invasion and normalized tumor necrosis factor alpha and IFN-gamma mRNA expression within the spinal cord. These data suggested that pharmacological intervention aimed at inhibiting proinflammatory cytokine expression within the central nervous system provided protection against BBB disruption, the first clinical sign of EAE and probably the key point of acute MS attacks. This finding could lead to the development of a new class of compounds for oral therapy of MS, as a supplement to immunosuppressive agents. 相似文献
18.
Mata M Glorioso JC Fink DJ 《The journals of gerontology. Series A, Biological sciences and medical sciences》2003,58(12):M1111-M1118
In the past 3 decades, gene therapy has moved from a theoretical construct to an active field of basic research, animal studies, and clinical trials. In this article, we describe the conceptual basis underlying the use of gene therapy for diseases of the aging nervous system, the principal techniques used for gene delivery, and review preclinical animal studies in 4 different classes of neurologic dysfunction: 1) focal neuronal degeneration in the central nervous system; 2) global neuronal dysfunction in the central nervous system; 3) degenerative disease affecting components of the peripheral nervous system; and 4) intractable focal pain. The full potential of this approach will not be established until the human trials are completed. 相似文献
19.
Plasmodium falciparum malaria is the most important parasitic disease infecting the central nervous system of humans worldwide. The pathogenesis of the neurological complications of falciparum malaria remains unclear. In particular, how do asexual parasites confined to the vascular space of the brain cause neuronal impairment? The evidence for a breakdown in the blood–brain barrier (BBB) is conflicting. In some animal models of malaria, there is evidence of breakdown of the BBB, but the data from humans suggests the BBB is mildly impaired only, with few morphological changes. Whether these changes in the BBB are sufficient to account for the neurological complications remains to be determined. 相似文献
20.
Infection of cultured central nervous system neurons with a defective herpes simplex virus 1 vector results in stable expression of Escherichia coli beta-galactosidase. 总被引:8,自引:3,他引:8
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A I Geller A Freese 《Proceedings of the National Academy of Sciences of the United States of America》1990,87(3):1149-1153