Genetically Modified Rhesus Monkeys

描述(申请人提供)：神经遗传疾病每年在美国导致数万人死亡，造成无法估量的痛苦和痛苦，并消耗稀缺的医疗资源的相当大一部分。这些疾病中的许多疾病并不存在对应的小鼠，因此有必要创建和使用新的哺乳动物模型。尽管发展神经遗传性疾病的猴子模型面临着巨大的挑战，但时机是合适的，需求也是迫切的。因此，我们的长期目标是培育出转基因恒河猴，作为人类神经遗传性疾病的模型。我们将集中于三种早发性、功能丧失的情况：Kallmann综合征、Lesch-Nyhan病和共济失调-毛细血管扩张症。我们将试图相对较快地建立这一范式，这是一个需要数十年才能显现出来的疾病无法实现的目标。由于Kallmann综合征和Lesch-Nyhan病是由于X染色体上的基因突变(分别为KAL1和HPRT)造成的，因此XY细胞突变只需要破坏一个等位基因就可以失去功能。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难度较大，但将建立在体外破坏常染色体基因所需的方法。我们的工作假设是，基因打靶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。这项应用的目标是建立必要的基础设施，以在培养中对恒河猴细胞进行基因改造，并将这些细胞用作核移植的捐赠者。然后，可以将所需基因的可存活胚胎转移到代孕母亲体内。将会产生转基因恒河猴。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的临床前模型，包括基于基因和干细胞的治疗。

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.