Disease-Modifying Genes in Huntington's Disease

亨廷顿病的疾病修饰基因

基本信息

批准号：
10381503
负责人：
JAMES F GUSELLA
金额：
$ 69.07万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10381503
关键词：
Address Affect Age Alleles Biological Biological Models Biological Process CAG repeat CRISPR/Cas technology Cell Line Cells Cessation of life Characteristics Chorea Clinical Clinical Trials Code Codon Nucleotides Cognitive Collaborations DNA Maintenance Process Data Diagnosis Disease Disease Progression Family Foundations Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genomic approach Glutamine Grant Haplotypes Home Human Human Genetics Huntington Disease Huntington gene Individual Inherited Intervention Knowledge Laboratories Lead Length Mediating Modification Motor Mutation Nature Neurodegenerative Disorders Neurons Onset of illness Participant Pathogenesis Pathway interactions Patients Pharmacologic Substance Phenotype Process Property Proteins RNA Regulation Reporting Resources Route Signal Transduction Societies Symptoms Testing Therapeutic Therapeutic Intervention Time Toxic effect Variant base clinical diagnosis cost disease phenotype effective therapy genetic approach genome-wide human data human model induced pluripotent stem cell mouse model new therapeutic target novel polyglutamine premature prevent sample collection success therapeutic development therapeutic target time interval

项目摘要

Disease-Modifying Genes in Huntington's Disease: HD is a devastating neurodegenerative disorder with a long, costly, debilitating course to premature death, ~15 yrs after clinical diagnosis. There is a dire need for effective therapies to alleviate the suffering and cost to the individual, family and society. The HD mutation in HTT is an expanded CAG trinucleotide repeat whose length is the main factor determining the timing of clinical onset. Although it is often assumed that the length of polyglutamine in huntingtin drives the rate of pathogenesis leading to HD onset, our data from HD subjects do not support this conclusion. Disease-associated HTT alleles with the same pure CAG repeat size may produce different-sized polyglutamine tracts due to variable glutamine-encoding CAA codons, with no commensurate hastening in HD onset due to extra glutamines. Rather, age-at-onset is best explained by a property of the pure CAG repeat separate from its coding potential. We have discovered that HD age-at-onset is modified by genetic variation at 6 loci that encode genes involved in a variety of DNA maintenance processes. These genetic modifiers, in both humans and mouse models, implicate somatic expansion of the CAG repeat rather than encoded polyglutamine as the factor determining age-at-onset. By contrast, symptomatic progression shows at best a weak correlation with CAG repeat size, while duration of manifest disease (i.e., the time from motor diagnosis to death) is independent of CAG repeat length, suggesting that other factors are paramount in determining pathogenesis from onset to death. Overall our findings point to HD as comprising two distinct components: 1) length-dependent somatic expansion of the CAG repeat up to and above a threshold length (rate driver) that then engages toxicity and 2) as yet uncertain mechanism(s) by which the somatically expanded repeat triggers damage when the threshold length is reached (toxicity driver). The nature of the toxicity driver(s) is not yet unequivocal. An effect on huntingtin by above-threshold polyglutamine (rather than continuous length-dependent toxicity) is both attractive and consistent with the effects of long CAG repeats in model systems, but other mechanisms that act at the transcriptional or RNA level have also been suggested as causative. The success of our human genetic strategy has begun to provide new targets for therapeutic interventions to delay or prevent HD onset. In this renewal, we will identify additional rate modifiers to more fully delineate the process of somatic CAG expansion in humans and will extend our strategy to discover modifiers of manifest disease that implicate the nature of the toxicity driver or its damaging consequences. The identification of novel targets, implicated by the natural variation in biological processes ongoing in HD subjects themselves, will provide a firm foundation for developing pharmaceutical interventions that push those processes even farther, toward a strong therapeutic benefit. Thus, the promise of this grant is a new and powerful route to fulfilling the greatest need of both premanifest and manifest HD subjects and their families: effective treatments to block or delay onset and progression of the disease.

亨廷顿舞蹈病的疾病修饰基因：亨廷顿舞蹈病是一种毁灭性的神经退行性疾病，具有长期、临床诊断后约 15 年，患者会经历昂贵且令人衰弱的过程直至过早死亡。迫切需要有效的减轻个人、家庭和社会的痛苦和成本的疗法。 HTT 中的 HD 突变是扩展的CAG三核苷酸重复序列的长度是决定临床发病时间的主要因素。尽管人们通常认为亨廷顿蛋白中聚谷氨酰胺的长度决定了发病率，导致对于 HD 发作，我们来自 HD 受试者的数据并不支持这一结论。与疾病相关的 HTT 等位基因由于谷氨酰胺编码可变，相同的纯 CAG 重复大小可能会产生不同大小的聚谷氨酰胺束 CAA 密码子，由于额外的谷氨酰胺，HD 发病没有相应的加速。相反，发病年龄是最好的解释是纯 CAG 重复序列与其编码潜力分开的特性。我们发现 HD 发病年龄受到 6 个基因座遗传变异的影响，这些基因座编码涉及多种 DNA 的基因维护流程。这些基因修饰剂在人类和小鼠模型中都涉及体细胞 CAG重复序列的扩增而不是编码的聚谷氨酰胺作为决定发病年龄的因素。经过相比之下，症状进展充其量与 CAG 重复大小存在弱相关性，而症状进展的持续时间明显疾病（即从运动诊断到死亡的时间）与 CAG 重复长度无关，表明其他因素在确定从发病到死亡的发病机制中至关重要。总的来说，我们的研究结果表明 HD 包含两个不同的组成部分：1) CAG 重复的长度依赖性体细胞扩展至和超过阈值长度（速率驱动因素），然后产生毒性；2）尚不确定的机制当达到阈值长度时，体细胞扩展的重复会触发损伤（毒性驱动因素）。这毒性驱动因素的性质尚未明确。阈值以上聚谷氨酰胺对亨廷顿蛋白的影响（而不是连续长度依赖性毒性）既有吸引力又与长 CAG 的效果一致在模型系统中重复，但在转录或 RNA 水平起作用的其他机制也已被研究建议作为因果关系。我们人类遗传策略的成功已经开始为延迟或预防 HD 发作的治疗干预措施。在此更新中，我们将确定其他费率调节因素更全面地描绘人类体细胞 CAG 扩张的过程，并将扩展我们的策略以发现涉及毒性驱动因素的性质或其破坏性后果的明显疾病的修饰语。这识别新靶标，这些靶标与 HD 受试者中正在进行的生物过程的自然变化有关它们本身将为开发推动这些过程的药物干预措施提供坚实的基础甚至更进一步，以获得强大的治疗效果。因此，这笔赠款的承诺是一条新的、强有力的途径满足HD患者及其家人的最大需求：有效的治疗阻止或延缓疾病的发生和进展。