Disease-Modifying Genes in Huntington's Diseae

 描述（由申请人提供）：亨廷顿氏病（HD）是一种破坏性神经退行性疾病，涉及运动、精神和认知障碍，存在于超过1/10，000的人中，但作为一种家族疾病，具有长期、昂贵、衰弱的病程，对更大比例的人口产生间接影响，给个人和社会带来巨大代价。虽然使用了一些姑息治疗，但目前没有有效的治疗方法来预防疾病的临床发作或延迟其不可避免的进展，即诊断后约15年的过早死亡。在过去的几十年里，遗传学提供了将HD基因定位到4号染色体的工具，并最终将其突变鉴定为一种大型蛋白质（称为亨廷顿蛋白）编码序列中的扩展CAG三核苷酸重复序列。扩展的HD CAG重复序列的长度与诊断性运动体征的出现呈负相关，但不能解释该表型中的所有变异，因为其他遗传因素也影响疾病过程。我们已经使用全基因组关联分析来确定人类基因组中具有疾病修饰遗传变异的区域，这些遗传变异可以改变欧洲血统人类患者运动开始时的年龄。在这些位置的实际修饰基因的鉴定将突出临床诊断之前发生的过程，以改变HD的过程，从而为传统药物开发提供新的、人类验证的靶点。我们的目标是利用现有的遗传数据，并对受试者进行有针对性的额外基因分型，以确定1）这些修饰剂是否也会改变认知和精神病发作; 2）与其他疾病中的遗传因素重叠; 3）显示可以提供干预靶点的途径/过程的富集。这些发现，在每个相关区域与密集的单倍型分析，测序和表达分析的基因座和候选基因的测试，在人类诱导多能干细胞和精确的遗传HD小鼠模型建立疾病相关的测定相结合，将收敛到识别的基因负责疾病的修改及其功能变异。这项工作的成果将是一个知识的特定基因和途径，可以延迟HD发病机制在人类患者，在何种程度上，他们广泛影响HD运动和其他表型和潜在的机制，他们的行动。我们还将提供必要的关键细胞和小鼠模型资源，以快速推动研究结果向HD社区转化。我们相信，新目标的确定， 由HD患者自身正在进行的生物过程中的自然变异所暗示的，将为开发有效的药物干预提供坚实的基础，以推动这些过程在HD患者中实现强大的治疗益处。因此，这笔赠款的承诺是满足HD患者和家庭最大需求的一条新的强有力的途径：一种有效的治疗方法，以延迟或预防疾病的发作。

 DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating neurodegenerative disorder involving motor, psychiatric and cognitive disturbances present in more than 1 in 10,000 persons but, as a family disorder with a long, costly, debilitating course, with an indirect impact on a far greater proportion of the population at great cost to the individul and society. While some palliative treatments are used, there is currently no effective treatment for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, ~15 years after diagnosis. In past decades, genetics provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. The length of the expanded HD CAG repeat is negatively correlated with the appearance of diagnostic motor signs but does not explain all of the variance in this phenotype, as other genetic factors also influence the disease process. We have used genome-wide association analysis to identify regions of the human genome which harbor disease-modifying genetic variation that acts to alter age at motor onset in human patients of European ancestry. Identification of the actual modifier genes at these locations will highlight processes occurring before clinical diagnosis to alter the course of HD and therefore to provide new, human-validated targets for traditional drug development. Our aims are to capitalize on existing genetic data and carry out focused additional genotyping of subjects to determine whether 1) these modifiers also modify cognitive and psychiatric onsets; 2) overlap with genetic factors in other disorders; and 3) show enrichment for pathways/processes that could provide targets for intervention. These findings, combined in each associated region with dense haplotyping, sequencing and expression analysis of the loci involved and testing of candidate genes in established disease-relevant assays in human induced pluripotent stem cells and precise genetic HD mouse models will converge to identification of the gene responsible for disease modification and its functional variation. The product of this work will be a knowledge of specific genes and pathways that can delay HD pathogenesis in human patients, of the degree to which they broadly affect both HD motor and other phenotypes and of the potential mechanisms by which they act. We will also provide critical cellular and mouse model resources necessary to rapidly drive the findings toward translation for the HD community. It is our belief that the identification of novel targets, implicated by the natural variation in biological processes ongoing in HD patients themselves, will provide a firm foundation for developing effective pharmaceutical interventions to push those processes toward a strong therapeutic benefit in HD patients. Thus, the promise of this grant is a new and powerful route to fulfilling the greatest need of HD patients and families: an effective treatment to delay of prevent onset of the disease.