Genetically Modified Rhesus Monkeys

神经遗传性疾病每年在美国造成数万人死亡，造成不可估量的疼痛和痛苦，并消耗了相当大一部分稀缺的医疗资源。许多这些疾病的小鼠对应物不存在，需要创建和使用新的哺乳动物模型。尽管与神经遗传性疾病的猴子模型的发展相关的重大挑战，时间是适当的，需要是迫切的。因此，我们的长期目标是生产转基因恒河猴，作为人类神经遗传性疾病的模型。我们将集中在三个，早发性，功能丧失的条件：卡尔曼氏综合征，莱施尼汉氏病和共济失调毛细血管扩张症。我们将尝试相对快速地建立范式，这一目标无法通过需要几十年才能揭示自己的疾病来实现。由于卡尔曼综合征和莱施-尼汉病是由于位于X染色体上的基因突变（分别为KAL 1和HPRT），XY细胞功能丧失突变只需要破坏一个等位基因。破坏常染色体共济失调毛细血管扩张症突变（ATM）基因的两个拷贝，虽然更困难，但将建立体外破坏常染色体基因所需的方法。我们的工作假设是，基因靶向和体细胞克隆技术相结合，可以为产生准确代表人类疾病的可靠动物供应提供基础。本申请的目的是建立必要的基础设施，对培养的恒河猴细胞进行遗传修饰，并将这些细胞用作核转移的供体。然后可以将所需基因型的所得存活胚胎转移到代孕母亲中。基因改造的恒河猴。这些动物应该为人类神经遗传性疾病的研究提供资源，并作为新的实验性治疗（包括基因和干细胞治疗）的临床前模型。

DESCRIPTION (provided by applicant): Neurogenetic diseases cause tens of thousands of deaths in the United States each year, inflict immeasurable pain and suffering, and consume a substantial portion of scarce healthcare resources. A mouse counterpart for many of these diseases does not exist necessitating the creation and use of new mammalian models. Despite the significant challenges associated with the development of monkey models of neurogenetic diseases, the time is appropriate and the need is compelling. Accordingly, our long-term goal is to produce genetically modified Rhesus monkeys that will serve as models for human neurogenetic diseases. We will focus on three, early-onset, loss of function conditions: Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. We will attempt to establish the paradigm relatively quickly, an objective that can not be met with diseases that require decades to reveal themselves. Because Kallmann's syndrome and Lesch-Nyhan's disease are due to mutations in genes located on the X chromosome (KAL1 and HPRT, respectively), loss of function XY cell mutations require disruption of only one allele. Disruption of the two copies of the autosomal Ataxia Telangiectasia Mutated (ATM) gene, while more difficult, will establish the methods necessary for disrupting autosomal genes in vitro. Our working hypothesis is that gene targeting and somatic cell cloning technology can, in combination, provide the basis for generating a reliable supply of animals that accurately represent human disease. The objective of this application is to create the infrastructure necessary to genetically modify Rhesus monkey cells in culture and to use those cells as donors for nuclear transfer. The resultant viable embryos of the desired genotype can then be transferred into surrogate mothers. Genetically modified Rhesus macaques will result. Such animals should provide a resource for the study of human neurogenetic diseases and serve as pre-clinical models for new experimental treatments including gene and stem cell based therapies.