Development of targeted therapeutic agents for the treatment of FXTAS (2 of 6)

开发治疗 FXTAS 的靶向治疗药物（2 of 6）

• 批准号: 7502189
• 负责人: PAUL J HAGERMAN
• 金额: $ 78.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502189
• 关键词: Adverse effects; Affect; Alleles; Antisense DNA; Astrocytes; Attenuated; Biochemical; CGG repeat; CGG repeat expansion; Cell model; Cell physiology; Cells; Cellular Morphology; Cellular Stress Response; Child; Classification; Clinical; Clinical Trials; Crystallins; Cytoplasm; Cytoskeleton; Development; Elements; Event; FMR1; FMR1 Gene; FMR1 Premutation; FXTAS; Foundations; Fragile X Syndrome; Functional disorder; Future; Gene Proteins; Glutamates; Human; Intervention; Lead; Lithium; Location; Mediating; Memantine; Mental Retardation; Methods; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neuropathy; Neurotransmitters; Nuclear; Oligonucleotides; Pathogenesis; Phenotype; Process; Proteins; RNA; Regulation; Research; Role; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Specific qualifier value; Synaptic Cleft; Testing; Tetanus Helper Peptide; Therapeutic Agents; Therapeutic Intervention; Time; Toxic effect; Transcriptional Activation; Transgenic Organisms; Up-Regulation; Viral; Work; base; cellular pathology; expectation; gain of function; improved; in vivo; interdisciplinary approach; knock-down; mouse model; neurodegenerative phenotype; neuropathology; neurophysiology; novel; novel therapeutics; relating to nervous system; research study; response; therapeutic target; uptake

Research under Project 1 of the Consortium will involve further study of neural cell models of the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The pathogenesis of FXTAS is the direct result of a toxic gain-of-function of excess FMR1 RNA that is produced from premutation CGG-repeat expansions of the fragile X mental retardation (FMR1) gene. The principal objective of this project will be the identification and assessment of various candidate therapeutic agents that m.ight attenuate the effects of the pathogenic RNA; through antisense-DNA- (ASO) or siRNA-mediated knock-down (Aims 1 and 2); through downstream effects of the neuropathic process, such as impaired glutamate regulation/uptake leading to glutamate toxicity (Aim 3); or through more proximal effects of the expanded- CGG-repeat RNA (Aim 4). Aims 1 and 2 will test the hypothesis that elimination of the RNA, either in neural cell models or in transgenic mouse models (Project 2), will at least partially reverse the pathogenic process. Studies using inducible cell models will test this hypothesis and, with Project 2, will develop expectations for future oligonucleotide-based therapies in humans. Based on clinical/pathological evidence (Projects 1 and 3) of clear astrocyte dysfunction in FXTAS, we will test our working hypothesis that glutamate dysregulation contributes to the neurodegeneration in FXTAS, as one component of these studies, we will test the effect of memantine in mixed neuronal/astrocyte murine cell models of FXTAS, in part to provide a cellular basis for the clinical trial of memantine in Project 3. The development of oligonucleotide-based therapeutic agents (ASO, siRNA) will involve two important elements. First, a systematic determination of the necessity of using ASOs, which can target nuclear as well as cytoplasmic RNA, or whether it is sufficient to use siRNA-based targeting to the cytoplasm. Second, together with Project 2, we will develop non-viral, CNS-targeted immunoliposomal delivery methods to deliver candidate ASO or siRNA oligos in vivo in mouse models (Project 2). During the course of these experiments, and in conjunction with Project 2, we will examine the timing and reversibility of the pathogenic response; this issue is important when considering the timing of therapeutic intervention for FXTAS. Finally, together with Projects 2 and 4, we will investigate the nature of developmental problems in children who are carriers of premutation alleles, to determine whether, as we suspect, their involvement represents a novel developmental phenotype due to RNA toxicity, represents an effect of slightly lower protein levels that would characterize a broad fragile X syndrome spectrum effect, or reflects a combination of both pathogenic mechanisms. This last issue provides an example of the true power of the interdisciplinary approach.

财团项目1下的研究将涉及进一步研究 神经退行性疾病，脆弱的X相关震颤/共济失调综合征（FXTA）。发病机理 FXTA是由Premunty产生的多余FMR1 RNA功能的直接结果 脆弱X智力低下（FMR1）基因的CGG重复扩展。主要目标 项目将是对M.ight衰减的各种候选治疗剂的识别和评估 致病性RNA的作用；通过反义DNA-（ASO）或siRNA介导的敲低（目标1） 和2）;通过神经性过程的下游效应，例如谷氨酸 调节/摄取导致谷氨酸毒性（AIM 3）；或通过扩展的更近端效应 CGG重复RNA（AIM 4）。目标1和2将检验以下假设：消除RNA，在神经中 细胞模型或转基因小鼠模型（项目2），至少将部分扭转致病过程。 使用可诱导细胞模型的研究将检验该假设，并且通过项目2，将提出对的期望 未来的基于寡核苷酸的疗法。基于临床/病理证据（项目1和3） 在FXTA中明确的星形胶质细胞功能障碍中，我们将测试谷氨酸失调的工作假设 作为这些研究的一部分，有助于FXTA中的神经退行性，我们将测试 混合神经元/星形胶质细胞鼠细胞模型中的美容，部分是为了提供细胞的基础 纪念在项目3中的临床试验。 基于寡核苷酸的治疗剂（ASO，siRNA）的开发将涉及两个重要的 元素。首先，系统地确定使用ASO的必要性，这也可以针对核 作为细胞质RNA，或者是否足以将基于siRNA的靶向细胞质靶向。第二， 与项目2一起，我们将开发非病毒，针对CNS的免疫脂质体递送方法 在小鼠模型中输送体内的候选ASO或siRNA寡素（项目2）。在这些过程中 实验以及与项目2结合的实验，我们将检查致病性的时间和可逆性 回复;考虑到FXTA的治疗干预时间时，此问题很重要。 最后，与项目2和4一起，我们将调查发育问题的性质 作为预告等位基因的载体的儿童，以确定我们怀疑的是他们的参与 代表由于RNA毒性引起的新型发育表型，代表略低的效果 蛋白质水平将表征广泛的脆弱X综合征谱效应或反映组合 两种致病机制。最后一个问题提供了一个真实力量的示例 跨学科方法。