Disease-Modifying Genes in Huntington's Disease

亨廷顿病的疾病修饰基因

• 批准号: 10614452
• 负责人: JAMES F GUSELLA
• 金额: $ 69.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10614452
• 关键词: 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; 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; 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

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.

亨廷顿氏病中的疾病改良基因：HD是一种毁灭性的神经退行性疾病，长期 临床诊断后约15年，使其衰弱的过程成本高昂。迫切需要有效 减轻个人，家庭和社会的苦难和成本的疗法。 HTT中的HD突变是 扩展的CAG三核苷酸重复，其长度是决定临床发作时间的主要因素。 尽管通常假定亨廷顿蛋白中的聚谷氨酰胺的长度驱动发病机理的速率 在高清发作中，我们来自高清主题的数据不支持此结论。与疾病相关的HTT等位基因 由于可变的谷氨酰胺编码，相同的纯CAG重复大小可能会产生不同大小 CAA密码子，由于额外的谷氨酰胺而没有相应的高清发作。相反，年龄是 最好用纯CAG重复的属性与其编码潜力分开解释。我们发现 高清年龄 - 通过6个基因座的遗传变异来改变，该基因座编码涉及多种DNA的基因 维护过程。这些遗传修饰符在人类和小鼠模型中都暗示了体细胞 CAG重复的扩展而不是编码聚谷氨酰胺作为确定年龄发病的因素。经过 对比，有症状的进展充其量与CAG重复大小相关，而持续时间 明显疾病（即从运动诊断到死亡的时间）独立于CAG重复长度，表明 这些因素在确定从发作到死亡的发病机理中至关重要。总的来说，我们的发现指向 HD作为两个不同的组成部分：1）CAG的长度依赖性体细胞膨胀重复到和 高于阈值长度（速率驱动器），然后引起毒性，2）尚不确定的机制 达到阈值长度时（毒性驱动器）时，体面扩展的重复触发会破坏。这 毒性驱动力的性质尚不明确。阈值多谷氨酰胺对亨廷顿的影响 （而不是连续的长度依赖性毒性）既有吸引力，又与长CAG的影响一致 在模型系统中重复，但是在转录或RNA水平上起作用的其他机制也已是 被认为是病因。我们人类遗传策略的成功已经开始为 治疗干预措施以延迟或预防高清发作。在此续订中，我们将确定其他费率修改器 更充分地描绘人类中躯体CAG扩展的过程，并将扩展我们的战略以发现 明显疾病的修饰符暗示毒性驱动力的性质或其破坏性后果。这 识别新靶标，与HD受试者中正在进行的生物学过程的自然变化有关 他们本身将为开发药物干预措施提供坚定的基础，以推动这些过程 甚至更远，要获得强大的治疗益处。因此，这笔赠款的承诺是一条新的强大途径 满足premifest和明显高清主题及其家人的最大需求：有效的治疗 阻止或延迟发作和进展。