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Antisense imaging of brain gene expression in vivo

Antisense imaging of brain gene expression in vivo
体内脑基因表达的反义成像
批准号:
6894945
负责人:
WILLIAM M PARDRIDGE
金额:
$32.41万
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-06-01 至 2006-05-31

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中文摘要
翻译
描述(由申请人提供): 人类基因组的序列将导致数以千计的 在脑癌和其他疾病中唯一表达的基因 器官。在脑癌中独特表达的基因可以用来指导 新形式的诊断和治疗策略,如果有可能 开发一种在活体内对大脑基因表达进行成像的新技术。 需要能够对基因表达进行成像的技术,因为它 将不可能使患者接受反复开颅手术以获得 组织样本。唯一可以对特定基因进行成像的方法是 反义放射性药物。然而,这些分子不会跨越细胞。 膜很好,不会越过血脑屏障(BBB)。可能会吧 有可能使用反义放射性药物来成像基因表达,如果 这些分子可以通过血脑屏障运输。这将需要 应用于反义分子的脑靶向技术的发展, 这是本申请的主题。在这种方法中, 反义放射性药物与BBB药物靶向系统偶联。这个 靶向载体是一种抗血脑屏障的多肽模拟单抗。 转铁蛋白受体(TFR)。这种单抗经历了受体介导的细胞转运。 通过内源性血脑屏障转铁蛋白受体途径血脑屏障。模型反义分子 将在这些研究中使用的是一种肽核酸(PNA),因为在 研究表明,这种类型的反义具有理想的特性 与其他反义分子进行成像比较。的共轭关系 便于针对药物靶向载体的反义放射性药物 通过使用亲和素-生物素技术。在这项工作的R21阶段, 将进行内源性基因的成像,目标mRNA将是一个 在实验性脑瘤中过度表达的基因产物。第二 这些研究的阶段(R33)将扩展成像技术,以包括[ 11 L-铟]反义放射性药物及其体内验证 原位杂交法平行体外测量成像。如果 这些研究的成功将为一种新技术提供基础, 能够对活体大脑中的基因表达进行非侵入性成像。这 技术可以扩展到人类和其他器官。目前,有 没有一种平行的技术能够实现非侵入性的体内成像 “任何人身上的任何基因”,这就是这项工作的目标。
英文摘要
DESCRIPTION (provided by applicant): The sequence of the human genome will lead to the detection of thousands of genes that are uniquely expressed in cancer of the brain as well as other organs. The genes uniquely expressed in brain cancer could be used to guide new forms of diagnosis and therapeutic strategies if it was possible to develop a new technology for imaging gene expression in the brain in vivo. Technology that enables the imaging of gene expression is needed because it will not be possible to subject patients to repeated craniotomies to obtain tissue samples. The only way that specific genes can be imaged is with antisense radiopharmaceuticals. However, these molecules do not cross cell membranes well and do not cross the blood-brain barrier (BBB). It could be possible to use antisense radiopharmaceuticals to image gene expression, if these molecules were transportable through the BBB. This will require the development of brain targeting technology applied to antisense molecules, which is the subject of the present application. In this approach, the antisense radiopharmaceutical is conjugated to BBB drug targeting systems. The targeting vector is a peptidomimetic monoclonal antibody (MAb) to the BBB transferrin receptor (TfR). This MAb undergoes receptor-mediated transcytosis through the BBB via the endogenous BBB TfR. The model antisense molecule that will be used in these studies is a peptide nucleic acid (PNA) because prior work has shown that this type of antisense has ideal characteristics for imaging compared to other antisense molecules. The conjugation of the antisense radiopharmaceuticals to the drug targeting vector is facilitated with the use of avidin- biotin technology. In the R21 phase of this work, the imaging of an endogenous gene will be performed and the target mRNA will be a gene product that is over-expressed in experimental brain tumors. The second phase of these studies (R33) will extend the imaging technologies to include [ 11 l-indium] antisense radiopharmaceuticals and validation of the in vivo imaging with parallel in vitro measurements with in situ hybridization. If successful, these studies will provide the basis for a new technology that enables non-invasive imaging of gene expression in the brain in vivo. This technology could be extended to humans and to other organs. At present, there is no parallel technology that enables the non-invasive in vivo imaging of "any gene in any person," which is the goal of this work.
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Non-Viral Gene Targeting to the Brain
Non-Viral Gene Targeting to the Brain
Antisense imaging of brain gene expression in vivo
Antisense imaging of brain gene expression in vivo
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