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 proposal 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 proposal. 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.
(provided by applicant): 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.
|Kunkanjanawan, Tanut; Carter, Richard; Ahn, Kwan-Sung et al. (2017) Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery. SLAS Discov 22:696-705|
|Moran, Sean P; Chi, Tim; Prucha, Melinda S et al. (2016) Cryotolerance of Sperm from Transgenic Rhesus Macaques (Macaca mulatta). J Am Assoc Lab Anim Sci 55:520-4|
|Moran, Sean; Chi, Tim; Prucha, Melinda S et al. (2015) Germline transmission in transgenic Huntington's disease monkeys. Theriogenology 84:277-85|
|Kocerha, Jannet; Xu, Yan; Prucha, Melinda S et al. (2014) microRNA-128a dysregulation in transgenic Huntington's disease monkeys. Mol Brain 7:46|
|Chan, Anthony Ws; Xu, Yan; Jiang, Jie et al. (2014) A two years longitudinal study of a transgenic Huntington disease monkey. BMC Neurosci 15:36|
|Chan, Anthony W S (2013) Progress and prospects for genetic modification of nonhuman primate models in biomedical research. ILAR J 54:211-23|
|Piotrowska-Nitsche, Karolina; Chan, Anthony W S (2013) Effect of sperm entry on blastocyst development after in vitro fertilization and intracytoplasmic sperm injection - mouse model. J Assist Reprod Genet 30:81-9|
|Laowtammathron, Chuti; Chan, Anthony W S (2013) Pluripotent hybrid stem cells from transgenic Huntington's disease monkey. Methods Mol Biol 1010:61-77|
|Putkhao, Kittiphong; Kocerha, Jannet; Cho, In-Ki et al. (2013) Pathogenic cellular phenotypes are germline transmissible in a transgenic primate model of Huntington's disease. Stem Cells Dev 22:1198-205|
|Cheng, Pei-Hsun; Li, Chia-Ling; Her, Lu-Shiun et al. (2013) Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein. Brain Struct Funct 218:283-94|
Showing the most recent 10 out of 29 publications