Genetically Modified Rhesus Monkeys

描述（由申请人提供）：神经遗传疾病每年在美国造成数万人死亡，造成无法估量的痛苦和痛苦，并消耗大量稀缺的医疗资源。许多这些疾病的小鼠对应物并不存在，因此需要创建和使用新的哺乳动物模型。尽管与神经遗传疾病的猴子模型的发展相关的重大挑战，时间是适当的，需要是令人信服的。因此，我们的长期目标是培育转基因恒河猴，作为人类神经遗传疾病的模型。我们将重点关注三种早发性功能丧失疾病：Kallmann综合征，Lesch-Nyhan病和共济失调-毛细血管扩张症。我们将尝试相对较快地建立范式，这一目标无法通过需要数十年时间才能显露出来的疾病来实现。由于Kallmann综合征和Lesch-Nyhan病是由于位于X染色体上的基因突变（分别为KAL1和HPRT）， XY细胞突变的功能丧失只需要一个等位基因的破坏。破坏常染色体共济失调毛细血管扩张突变（ATM）基因的两个拷贝虽然比较困难，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，可以为产生可靠的动物供应提供基础，准确地代表人类疾病。这项申请的目的是创造必要的基础设施，在培养中对恒河猴细胞进行基因修饰，并将这些细胞用作核移植的供体。由此产生的符合所需基因型的可存活胚胎可以移植到代孕母亲体内。转基因恒河猴将由此诞生。这些动物应该为人类神经遗传疾病的研究提供资源，并作为包括基因和干细胞治疗在内的新实验治疗的临床前模型。

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.