Establishment of a transgenic monkey model of Huntington's disease

描述（由申请人提供）：非人灵长类动物（NHPs；猴子）在生物医学研究的许多领域做出了重大贡献，因为它们是研究人类疾病的宝贵模型。最近转基因技术的进步导致了亨廷顿氏病（HD）的第一个转基因猴子模型的创建。转基因HD猴子会出现与人类患者相似的神经病变，这在啮齿类动物模型中很少观察到。除了突变亨廷顿蛋白（htt）对猴子的神经毒性外，HD猴子还会出现与HD患者相似的不自主运动和协调身体运动困难。我们已经成功地实现了最初提出的目标，即开发一种表达突变htt的转基因HD猴子，并产生与人类患者相似的症状。我们一共培育了5只足月出生的转基因猴，它们都是htt和绿色荧光蛋白基因突变的双转基因猴。其中三只HD猴婴儿表现出严重的舞蹈病和肌张力障碍症状。其中两名存活了一天，第三名存活了一个月。他们的临床症状和疾病严重程度的差异表明CAG重复次数、整合事件数量和htt片段大小的影响。我们的目标是继续描述现有的两只高清猴子，目前十个月大，以及新一代高清猴子，预计在父母提案的最后一个预算年度。因此，一批HD猴子创始人将被建立起来。该应用程序旨在通过非侵入性成像和认知行为测试继续监测HD猴子群体中的疾病发展，并监测HD的进展。本应用程序的主要目标是对HD猴进行深入表征，并建立具有已知基因型和表型的HD猴队列。我们将评估HD猴子模型是否比啮齿动物模型更好地概括人类HD。我们还制定了建立HD猴子队列的计划，这将用于HD研究界。我们的三个具体目标是：(1)评估转基因HD猴的表型特征；(2)评估转基因HD猴的分子和细胞特征；(3)HD猴精子和胚胎的冷冻保存。

DESCRIPTION (provided by applicant): Nonhuman primates (NHPs; monkeys) have contributed significantly in many areas of biomedical research as they are invaluable models for studying human diseases. Recent advancements in transgenic technology have resulted in the creation of the first transgenic monkey model of Huntington's disease (HD). Transgenic HD monkeys develop neuropathologies similar to that of human patients, which are rarely observed in rodent models. Besides the neurotoxicity of mutant huntingtin (htt) in monkeys, HD monkeys also develop involuntary movement and difficulties in coordinating body movement similar to that of HD patients. We have successfully accomplished our goal of the original proposal in developing a transgenic HD monkey that expresses mutant htt and develops symptoms comparable to human patients. We have generated a total of five transgenic monkeys that were born at full term and they were all double transgenic with mutant htt and green fluorescent protein genes. Three of the HD monkey infants exhibited severe signs of chorea and dystonia. Two survived for one day and the third for one month. The variations in their clinical symptoms and the severity of the disease suggest the effect of the number of CAG repeats, the number of integration events, and the size of the htt fragment. Our objective is to continue characterizing the two existing HD monkeys, currently ten months old, and the new generation of HD monkeys that are expected in the last budgeted year of the parent proposal. Thus a cohort of HD monkey founders will be established. This application aims to continue monitoring disease development among the cohort of HD monkeys and monitoring HD progression by non-invasive imaging and cognitive behavioral tests. The primary goals of this application are to perform in-depth characterization on HD monkeys and establish a cohort of HD monkeys with known genotypes and phenotypes. We will evaluate if the HD monkey model is a better model to recapitulate HD in humans than a rodent model. We have also laid out a plan for establishing a cohort of HD monkeys, which will be available for the HD research community. Our three specific aims are: (1) Assessment of phenotypic characteristics in transgenic HD monkeys, (2) Assessment of molecular and cellular characteristics in transgenic HD monkeys, and (3) Cryopreservation of HD monkey's spermatozoa and embryos. PUBLIC HEALTH RELEVANCE (provided by applicant): This study is to continue characterizing transgenic HD monkeys and determines if a transgenic monkey model has privileged of modeling human inherited neurodegenerative diseases compared to the other animal models. A strategic plan is also developed for the establishment of a cohort of the HD monkey, which will be available for the HD research community.