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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-ETTN-G (13))
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Gwinn, Katrina
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Exemplar Genetics, LLC
Sioux Center
United States
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Beraldi, Rosanna; Meyerholz, David K; Savinov, Alexei et al. (2017) Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease. Biochim Biophys Acta Mol Basis Dis 1863:2862-2870
Rogers, Christopher S (2016) Engineering Large Animal Species to Model Human Diseases. Curr Protoc Hum Genet 90:15.9.1-15.9.14