Development of a Porcine Model of Ataxia-Telangiectasia

Information

  • Research Project
  • 8496150
  • ApplicationId
    8496150
  • Core Project Number
    R44NS076075
  • Full Project Number
    5R44NS076075-03
  • Serial Number
    076075
  • FOA Number
    PA-11-096
  • Sub Project Id
  • Project Start Date
    8/15/2011 - 13 years ago
  • Project End Date
    6/30/2015 - 9 years ago
  • Program Officer Name
    GWINN, KATRINA
  • Budget Start Date
    7/1/2013 - 11 years ago
  • Budget End Date
    6/30/2015 - 9 years ago
  • Fiscal Year
    2013
  • Support Year
    03
  • Suffix
  • Award Notice Date
    6/5/2013 - 11 years ago
Organizations

Development of a Porcine Model of Ataxia-Telangiectasia

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.

IC Name
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
  • Activity
    R44
  • Administering IC
    NS
  • Application Type
    5
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    608209
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    853
  • Ed Inst. Type
  • Funding ICs
    NINDS:608209\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    EXEMPLAR GENETICS, LLC
  • Organization Department
  • Organization DUNS
    808053784
  • Organization City
    SIOUX CENTER
  • Organization State
    IA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    512502029
  • Organization District
    UNITED STATES