Development of a Porcine Model of Ataxia-Telangiectasia

共济失调毛细血管扩张猪模型的建立

• 批准号: 8393247
• 负责人: Christopher Rogers
• 金额: $ 60.32万
• 依托单位: EXEMPLAR GENETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393247
• 关键词: ATM function; ATM gene; Affect; Anatomy; Animal Model; Animals; Ataxia Telangiectasia; Biochemical; Biological Assay; Brain; Brain Neoplasms; Breeding; Cells; Chromosomal Instability; Clinical; Complex; Defect; Development; Diabetes Mellitus; Disease; Early Onset Cerebellar Ataxia; Embryo; Engineering; Exhibits; Failure; Family suidae; Female; Fibroblasts; Functional disorder; Gene Targeting; Generations; Genes; Globulins; Goals; Growth; Heterozygote; Human; Immune system; Immunologic Deficiency Syndromes; Inborn Genetic Diseases; Individual; Industry; Injection of therapeutic agent; Insulin Resistance; Ionizing radiation; Malignant Neoplasms; Medical; Mission; Modeling; Molecular; Motor; Mus; Mutation; Names; Nature; Neurologic; Nuclear; Organ; Pathogenesis; Patients; Phase; Phenotype; Physical therapy; Physiological; Physiology; Predisposition; Pregnancy; Proteins; Research Personnel; Resources; Series; Source; Speech Therapy; Symptoms; Testing; Therapeutic; Thymus Gland; Xenograft procedure; ataxia telangiectasia mutated protein; base; fetal; human disease; improved; leukemia/lymphoma; male; mouse model; mutant; novel diagnostics; novel therapeutics; nuclear transfer; progenitor; somatic cell nuclear transfer; symptom management; tool

DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a multi-systemic, recessively inherited disorder that affects between 1 in 40,000 to 1 in 100,000 individuals worldwide. It is characterized primarily by early onset cerebellar ataxia and telangiectasia, from which the disease name is derived. In addition, patients also exhibit a number of other clinical symptoms including increased susceptibility to cancer (lymphomas, leukemia, brain tumors), immunodeficiency, insulin-resistant diabetes, chromosomal instability, sensitivity to ionizing radiation, susceptibility to bronchopulmonary disease, and the absence, or almost complete absence, of a thymus. Current treatments for A-T are directed toward the management of symptoms. Physical and speech therapy can improve the lives of patients, and ¿-globulin injections can be given to support the immune system. However, no treatment is directed at the underlying defect. Consequently, A-T remains a fatal disease. The development of improved therapies for A-T is currently limited by the lack of an animal model that fully, and accurately, recapitulates the multi-systemic nature of this disease. A number of mouse models of A-T have been developed over the years by the targeted disruption of the mouse Atm gene, and these models have proved invaluable for studying some aspects of ATM function and A-T disease. However, no single mouse model fully replicates the complex clinical symptoms observed in human disease, and more importantly, none of the murine models develop the severe neurological phenotype that is the hallmark of human A-T disease. The failure of mouse models to develop the classical symptoms of A-T is likely the result of physiological, anatomical, and developmental differences between the two species. In contrast, pigs may serve as a better model in which to study human disease given that their development, anatomy, and physiology are more closely related to that of humans. Given that the development and anatomy of the pig brain more closely resembles that of humans than mice, mutations in the porcine ATM gene may result in many of the same neurological changes that are observed in A-T patients. Therefore, the ultimate goal of this proposal is to develop and commercialize a porcine model of A-T by disrupting the ATM gene. We intend to accomplish this in two steps by combining gene-targeting and somatic cell nuclear transfer (SCNT). In this proposal, ATM+/- fetal fibroblasts that were developed in Phase I will be used as nuclear donors for somatic cell nuclear transfer. Nuclear transfer embryos will be transferred to recipient females for gestation. Resulting piglets will have one targeted ATM gene. We will breed heterozygotes to produce ATM-/- pigs and perform a thorough molecular, biochemical, and physiological characterization. Finally, we will establish long-term breeding herds. This project is intended to produce a porcine model of ataxia-telangiectasia that will provide academic and industry researchers with an opportunity to better understand the consequences of ATM dysfunction, the pathogenesis of A-T disease, and provide an improved model in which to develop and test new therapeutic strategies. PUBLIC HEALTH RELEVANCE: This proposal specifically outlines the development, initial characterization, and propagation of genetically engineered porcine model of the human disease, ataxia-telangiectasia. This project is relevant to the NIH's mission because it will provide a resource to stimulate discovery, therapeutic application, and the development of new diagnostic tools.

描述（由申请人提供）：共济失调-毛细血管扩张症（a-t）是一种多系统的隐性遗传疾病，在全球范围内的发病率为1 / 40,000至1 / 100,000。其主要特征是早发性小脑性共济失调和毛细血管扩张，由此得名。此外，患者还表现出许多其他临床症状，包括对癌症（淋巴瘤、白血病、脑肿瘤）的易感性增加、免疫缺陷、胰岛素抵抗型糖尿病、染色体不稳定、对电离辐射敏感、对支气管肺疾病的易感性以及胸腺缺失或几乎完全缺失。目前对A-T的治疗是针对症状的管理。物理和语言治疗可以改善病人的生活，可以注射-球蛋白来支持免疫系统。然而，没有针对潜在缺陷的治疗。因此，a - t仍然是一种致命的疾病。目前，由于缺乏一种能够全面、准确地概括这种疾病的多系统性质的动物模型，改进A-T治疗方法的发展受到限制。多年来，通过靶向破坏小鼠Atm基因，已经开发了许多小鼠A- t模型，这些模型对于研究Atm功能和A- t疾病的某些方面具有宝贵的价值。然而，没有一个单一的小鼠模型完全复制在人类疾病中观察到的复杂临床症状，更重要的是，没有一个小鼠模型表现出严重的神经表型，这是人类A-T疾病的标志。小鼠模型未能出现A-T的经典症状，可能是两种物种之间生理、解剖和发育差异的结果。相比之下，由于猪的发育、解剖和生理与人类更密切相关，因此猪可能是研究人类疾病的更好模型。考虑到猪大脑的发育和解剖结构比老鼠更接近人类，猪ATM基因的突变可能导致许多在A-T患者中观察到的相同的神经系统变化。因此，本提案的最终目标是通过破坏ATM基因来开发和商业化猪a - t模型。我们打算通过结合基因靶向和体细胞核移植（SCNT）两步来实现这一目标。在这个建议中，ATM+/-胎儿成纤维细胞