Establishment of a transgenic monkey of Huntingtons's diesease

Summary

Principal Investigator: Anthony Wing Sang Chan
Affiliation: Emory University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Nonhuman primates (NHPs;monkeys) have contributed significantly in many areas of biomedical research as they are invaluable models for studying human diseases. Recent advancements in transgenic technology have resulted in the creation of the first transgenic monkey model of Huntington's disease (HD). Transgenic HD monkeys develop neuropathologies similar to that of human patients, which are rarely observed in rodent models. Besides the neurotoxicity of mutant huntingtin (htt) in monkeys, HD monkeys also develop involuntary movement and difficulties in coordinating body movement similar to that of HD patients. We have successfully accomplished our goal of the original application in developing a transgenic HD monkey that expresses mutant htt and develops symptoms comparable to human patients. We have generated a total of five transgenic monkeys that were born at full term and they were all double transgenic with mutant htt and green fluorescent protein genes. Three of the HD monkey infants exhibited severe signs of chorea and dystonia. Two survived for one day and the third for one month. The variations in their clinical symptoms and the severity of the disease suggest the effect of the number of CAG repeats, the number of integration events, and the size of the htt fragment. Our objective is to continue characterizing the two existing HD monkeys, currently ten months old, and the new generation of HD monkeys that are expected in the last budgeted year of the parent application. Thus a cohort of HD monkey founders will be established. This application aims to continue monitoring disease development among the cohort of HD monkeys and monitoring HD progression by non-invasive imaging and cognitive behavioral tests. The primary goals of this application are to perform in-depth characterization on HD monkeys and establish a cohort of HD monkeys with known genotypes and phenotypes. We will evaluate if the HD monkey model is a better model to recapitulate HD in humans than a rodent model. We have also laid out a plan for establishing a cohort of HD monkeys, which will be available for the HD research community. Our three specific aims are: (1) Assessment of phenotypic characteristics in transgenic HD monkeys, (2) Assessment of molecular and cellular characteristics in transgenic HD monkeys, and (3) Cryopreservation of HD monkey's spermatozoa and embryos. RELEVANCE (See instructions): This study is to continue characterizing transgenic HD monkeys and determines if a transgenic monkey model has privileged of modeling human inherited neurodegenerative diseases compared to the other animal models. A strategic plan is also developed for the establishment of a cohort of the HD monkey, which will be available for the HD research community.
Funding Period: ----------------2003 - ---------------2014-
more information: NIH RePORT

Top Publications

  1. pmc Postnatal stem/progenitor cells derived from the dental pulp of adult chimpanzee
    Pei Hsun Cheng
    Neuroscience Division, Yerkes National Primate Research Center, Atlanta, USA
    BMC Cell Biol 9:20. 2008
  2. doi Pluripotent hybrid stem cells from transgenic Huntington's disease monkey
    Chuti Laowtammathron
    Stem Cell and Developmental Biology 6, Genome Institute of Singapore, Genome, Singapore
    Methods Mol Biol 1010:61-77. 2013
  3. pmc Effect of sperm entry on blastocyst development after in vitro fertilization and intracytoplasmic sperm injection - mouse model
    Karolina Piotrowska-Nitsche
    Yerkes National Primate Research Center, 954 Gatewood Rd, N E, Atlanta, GA 30329, USA
    J Assist Reprod Genet 30:81-9. 2013
  4. pmc Pathogenic cellular phenotypes are germline transmissible in a transgenic primate model of Huntington's disease
    Kittiphong Putkhao
    Yerkes National Primate Research Center, Atlanta, Georgia, USA
    Stem Cells Dev 22:1198-205. 2013
  5. pmc Pluripotent stem cells models for Huntington's disease: prospects and challenges
    Richard L Carter
    Yerkes National Primate Research Center, 954 Gatewood Rd, N E Atlanta, GA 39329, USA
    J Genet Genomics 39:253-9. 2012
  6. pmc A two years longitudinal study of a transgenic Huntington disease monkey
    Anthony Ws Chan
    Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia
    BMC Neurosci 15:36. 2014
  7. doi Development of single mouse blastomeres into blastocysts, outgrowths and the establishment of embryonic stem cells
    Chanchao Lorthongpanich
    Yerkes National Primate Research Center, Department of Human Genetics and Genetics and Molecular Biology Program, Emory University School of Medicine, North East Atlanta, Georgia 30329, USA
    Reproduction 135:805-13. 2008
  8. pmc Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease
    Chuan En Wang
    Department of Human Genetics, Emory University School ofMedicine, Atlanta, GA 30322, USA
    Hum Mol Genet 17:2738-51. 2008
  9. ncbi Putative dental pulp-derived stem/stromal cells promote proliferation and differentiation of endogenous neural cells in the hippocampus of mice
    Anderson Hsien Cheng Huang
    Grace Dental Clinic, Kaohsiung City, Taiwan
    Stem Cells 26:2654-63. 2008
  10. pmc Chemical enhancement in embryo development and stem cell derivation from single blastomeres
    Chanchao Lorthongpanich
    Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, USA
    Cloning Stem Cells 10:503-12. 2008

Scientific Experts

  • Anthony Ws Chan
  • DARWIN JOHNSON PROCKOP
  • Karolina Piotrowska-Nitsche
  • Chuti Laowtammathron
  • Brooke R Snyder
  • Shang Hsun Yang
  • Pei Hsun Cheng
  • Chanchao Lorthongpanich
  • Rangsun Parnpai
  • Anderson Hsien Cheng Huang
  • Kittiphong Putkhao
  • Richard L Carter
  • Jinjing Yang
  • Jun Liu
  • Zoe R Donaldson
  • Chuan En Wang
  • Jannet Kocerha
  • In Ki Cho
  • Larry J Young
  • Dong Wu
  • Liya Wang
  • Eric C H Cheng
  • Hui Mao
  • Robert C Long
  • Shihua Li
  • Chris C Ibegbu
  • Robert T Sullivan
  • Adam L Orr
  • Michael R Hayden
  • Xiao Jiang Li
  • Rona K Graham
  • James W Thomas
  • Dimitri Fillos
  • Suzanne Tydlacka

Detail Information

Publications20

  1. pmc Postnatal stem/progenitor cells derived from the dental pulp of adult chimpanzee
    Pei Hsun Cheng
    Neuroscience Division, Yerkes National Primate Research Center, Atlanta, USA
    BMC Cell Biol 9:20. 2008
    ....
  2. doi Pluripotent hybrid stem cells from transgenic Huntington's disease monkey
    Chuti Laowtammathron
    Stem Cell and Developmental Biology 6, Genome Institute of Singapore, Genome, Singapore
    Methods Mol Biol 1010:61-77. 2013
    ..In order to create personal pluripotent stem cells from HD monkeys, here we present a tetraploid technique for deriving pluripotent hybrid HD monkey stem cells...
  3. pmc Effect of sperm entry on blastocyst development after in vitro fertilization and intracytoplasmic sperm injection - mouse model
    Karolina Piotrowska-Nitsche
    Yerkes National Primate Research Center, 954 Gatewood Rd, N E, Atlanta, GA 30329, USA
    J Assist Reprod Genet 30:81-9. 2013
    ..To investigate whether in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), influence the embryo's development and its quality using the mouse as a model...
  4. pmc Pathogenic cellular phenotypes are germline transmissible in a transgenic primate model of Huntington's disease
    Kittiphong Putkhao
    Yerkes National Primate Research Center, Atlanta, Georgia, USA
    Stem Cells Dev 22:1198-205. 2013
    ....
  5. pmc Pluripotent stem cells models for Huntington's disease: prospects and challenges
    Richard L Carter
    Yerkes National Primate Research Center, 954 Gatewood Rd, N E Atlanta, GA 39329, USA
    J Genet Genomics 39:253-9. 2012
    ..We also highlight the prospective application of Huntington's disease stem cell models in the development of novel therapeutic strategies and advancement of personalized medicine...
  6. pmc A two years longitudinal study of a transgenic Huntington disease monkey
    Anthony Ws Chan
    Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia
    BMC Neurosci 15:36. 2014
    ..This is the first study on a primate model of human HD based on longitudinal clinical measurements...
  7. doi Development of single mouse blastomeres into blastocysts, outgrowths and the establishment of embryonic stem cells
    Chanchao Lorthongpanich
    Yerkes National Primate Research Center, Department of Human Genetics and Genetics and Molecular Biology Program, Emory University School of Medicine, North East Atlanta, Georgia 30329, USA
    Reproduction 135:805-13. 2008
    ..Our results demonstrate that sister BTMs of an early embryo are not equally competent for ICM marker expression. However, we demonstrated the feasibility of establishing ES cells from a single BTM of outbred mice...
  8. pmc Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease
    Chuan En Wang
    Department of Human Genetics, Emory University School ofMedicine, Atlanta, GA 30322, USA
    Hum Mol Genet 17:2738-51. 2008
    ....
  9. ncbi Putative dental pulp-derived stem/stromal cells promote proliferation and differentiation of endogenous neural cells in the hippocampus of mice
    Anderson Hsien Cheng Huang
    Grace Dental Clinic, Kaohsiung City, Taiwan
    Stem Cells 26:2654-63. 2008
    ..Disclosure of potential conflicts of interest is found at the end of this article...
  10. pmc Chemical enhancement in embryo development and stem cell derivation from single blastomeres
    Chanchao Lorthongpanich
    Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, USA
    Cloning Stem Cells 10:503-12. 2008
    ..Our results suggest that ACTH can enhance the derivation of ES cells from single blastomere-derived embryos...
  11. doi Lentiviral integration preferences in transgenic mice
    Shang Hsun Yang
    Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road N E, Atlanta, GA 30329, USA
    Genesis 46:711-8. 2008
    ..Our findings suggested that lentiviruses were biased to integrate into the intragenic regions of early embryonic genome of mouse...
  12. ncbi Assisted fertilization and embryonic axis formation in higher primates
    Karolina Piotrowska-Nitsche
    Yerkes National Primate Research Centre, 954 Gatewood Road NE, Atlanta, Georgia 30329, USA
    Reprod Biomed Online 18:382-90. 2009
    ..As there are no studies to date regarding sperm entry in human oocytes and its influence on embryonic development, this investigation using the rhesus macaque as a clinical model is noteworthy...
  13. pmc Characterization of dental pulp stem/stromal cells of Huntington monkey tooth germs
    Brooke R Snyder
    Yerkes National Primate Research Center, 954 Gatewood Rd, NE Atlanta, GA 30329, USA
    BMC Cell Biol 12:39. 2011
    ..However, the properties of DPSCs from individuals with an inherited genetic disorder, such as Huntington's disease (HD), have not been fully investigated...
  14. pmc Reprogramming Huntington monkey skin cells into pluripotent stem cells
    Anthony W S Chan
    Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA
    Cell Reprogram 12:509-17. 2010
    ....
  15. pmc Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington's disease
    Brooke R Snyder
    Yerkes National Primate Research Center, Atlanta, Georgia, United States of America
    PLoS ONE 5:e9347. 2010
    ..We hypothesized that hMSCs would be beneficial in a mouse model of Huntington disease (HD) due to these neurogenic effects...
  16. pmc Noninvasive monitoring of embryonic stem cells in vivo with MRI transgene reporter
    Jun Liu
    Neuroscience Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA
    Tissue Eng Part C Methods 15:739-47. 2009
    ..The compatibility and functionality of ferritin as a reporter in mES cells opens up the possibility of using MRI for longitudinal noninvasive monitoring of ES cell-derived cell grafts at both molecular and cellular levels...
  17. pmc Production of germline transgenic prairie voles (Microtus ochrogaster) using lentiviral vectors
    Zoe R Donaldson
    Program in Neuroscience, Emory University, Atlanta, Georgia, USA
    Biol Reprod 81:1189-95. 2009
    ..This technology has the potential to allow investigation of specific gene candidates in prairie voles and provides a general protocol to pursue germline transgenic manipulation in many different rodent species...
  18. pmc Generation of transgenic monkeys with human inherited genetic disease
    Anthony W S Chan
    Yerkes National Primate Research Center, Emory University, Rm 2212 Neuroscience Bldg, 954 Gatewood Rd, N E, Atlanta, GA 30329, USA
    Methods 49:78-84. 2009
    ..We focused on the procedures in creating transgenic Huntington's disease monkeys, but our work can be applied to transgenesis in other nonhuman primate species...
  19. pmc Monkey hybrid stem cells develop cellular features of Huntington's disease
    Chuti Laowtammathron
    Yerkes National Primate Research Center, 954 Gatewood Rd, NE Atlanta, GA 39329, USA
    BMC Cell Biol 11:12. 2010
    ..Additionally, a Huntington's cell model that develops robust pathological features of Huntington's disease would be valuable for drug discovery research...