Production of Transgenic Nonhuman Primates

Chan, Anthony W.S.; Chong, Kowit-Yu; Schatten, Gerald

doi:10.1016/b978-0-12-410490-7.00014-1

Cited by 4 publications

(16 citation statements)

References 353 publications

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“…HD and WT-Control monkeys were chair trained for semen collection using IACUC approved electroejaculation protocol [20,21,23]. Expanded blastocysts were selected for inner cell mass (ICM) isolation by using XYClone laser (Hamilton Throne, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…In vitro maturation [21,23] Oocytes were matured in modified CMRL-1066 containing 10% heat-inactivated fetal bovine serum (FBS; Hyclone Laboratories, Inc.) supplemented with 40 mg/mL Sodium pyruvate, 150 mg/mL Glutamine, 550 mg/mL Calcium lactate, 100 ng/mL estradiol, and 3 mg/mL of Progesterone for up to 36 h in 35-mL drops of medium under mineral oil at 37°C with 5% CO 2 , 5% O 2 , and 90% N 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Regimen of follicular stimulation [21,23] Female rhesus monkeys exhibiting regular menstrual cycles were induced with exogenous gonadotropins. On day 1 or 2 of menses, subcutaneous human follicle-stimulating hormone [r-FSH: Organon Inc. 30 IU, intramuscular injection (IM)] was injected twice daily for 6 days.…”

Section: Methodsmentioning

confidence: 99%

“…Production of transgenic HD monkey embryos and establishment of ESCs [21,[23][24][25] MII arrested oocytes were retrieved from hormonestimulated female rhesus macaques and used for in vitro fertilization by intracytoplasmic sperm injection (ICSI) followed by in vitro culture using HECM-9 [24]. HD and WT-Control monkeys were chair trained for semen collection using IACUC approved electroejaculation protocol [20,21,23].…”

Section: Methodsmentioning

confidence: 99%

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Pathogenic Cellular Phenotypes are Germline Transmissible in a Transgenic Primate Model of Huntington's Disease

Putkhao

Kocerha

Cho

et al. 2013

Stem Cells and Development

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A transgenic primate model for Huntington's Disease (HD) first reported by our group that (HD monkeys) carry the mutant Huntingtin (HTT) gene with expanded polyglutamine (CAG) repeats and, develop chorea, dystonia, and other involuntary motor deficiencies similar to HD [1]. More recently, we have found that longitudinal magnetic resonance imaging of the HD monkey brain revealed significant atrophy in regions associated with cognitive deficits symptomatic in HD patients, providing the first animal model which replicates clinical phenotypes of diagnosed humans. Here we report germline transmission of the pathogenic mutant HTT in HD monkey by the production of embryos and subsequent derivation of HD monkey embryonic stem cells (rHD-ESCs) using HD monkey sperm. rHD-ESCs inherit mutant HTT and green fluorescent protein (GFP) genes through the gametes of HD monkey. rHD-ESCs express mutant HTT and form intranuclear inclusion, a classical cellular feature of HD. Notably, mosaicism of the pathogenic polyQ region in the sperm as well as derived ESCs were also observed, consistent with intraindividual and intergenerational reports of mosaic CAG repeats [2,3]and CAG expansion in HD patients [4][5][6][7]. The confirmation of transgene inheritability and development of pathogenic HD phenotype in derived rHD-ESCs reported in this study is a milestone in the pursuit of a transgenic primate model with inherited mutant HTT for development of novel disease biomarkers and therapeutics.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Pathogenic Cellular Phenotypes are Germline Transmissible in a Transgenic Primate Model of Huntington's Disease

Putkhao

Kocerha

Cho

et al. 2013

Stem Cells and Development

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“…3,10,[14][15][16][17][18] The development of a new animal model is not only important for a better understanding of human diseases, but also important for the development of diagnostic tools and treatments. 18,19 Unfortunately, animals that carry genetic defects similar to those found in patients do not develop identical patterns. [20][21] This suggests fundamental differences between human and other mammalian species such as rodents and nonhuman primates (NHPs).…”

Section: Introductionmentioning

confidence: 97%

Transgenic Animal Models of Neurodegenerative Diseases

Chan

Ağca

Sourcebook of Models for Biomedical Research

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Neurodegenerative diseases are complex disorders involving neuropathological and psychiatric alterations. Transgenic mice expressing mutant human Alzheimer precursor protein (βAPP), α-synuclein, and mutant huntingtin genes have been developed for Alzheimer's, Parkinson's, and Huntington's disease (AD, PD, and HD), respectively. However, none of the existing mouse models completely represents the pathology of these diseases, including neuronal loss, cerebral atrophy, widespread neurofi brillary tangles, and neuropil threads in AD, formation of Lewy bodies and the extensive loss of dopaminergic neurons in PD, and neuronal loss and aggregate formation in HD. Although rat models have been shown to be superior to mouse models because of the brain size and the availability of more sophisticated behavioral testing, a common disadvantage in rodent models is the lack of neurodegeneration. Furthermore, rodents have relatively smaller brains and thus provide a limited behavioral repertoire for assessing transgene-associated structural and cognitive deficits. Nonhuman primates are ideally suited for modeling the neuropathology of neurodegenerative diseases because of their biological proximity to humans, size, and age-related development of lesions. Thus the development of a transgenic nonhuman primate model of neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Nevertheless, it is undeniable that rodent models contribute significantly to the understanding of neurodegenerative diseases and the development of cures. A transgenic nonhuman primate model will be able to mimic human conditions not only physiologically but also genetically. However, the development of transgenic rodent and nonhuman primate models of neurodegenerative diseases is equally important for unraveling the mystery of neurodegeneration and the development of early diagnosis and cures.

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Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

et al. 2017

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Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion of CAG trinucleotide repeat (polyglutamine; polyQ) in the huntingtin (HTT) gene which leads to the formation of mutant HTT (mHTT) protein aggregates. In the nervous system, an accumulation of mHTT protein results in glutamate-mediated excitotoxicity, proteosome instability and apoptosis. Although HD pathogenesis has been extensively studied, effective treatment of HD has yet to be developed. Therapeutic discovery research in HD has been reported using yeast, cells derived from transgenic animal models and HD patients and induced pluripotent stem cell (iPSCs) from patients. A transgenic nonhuman primate model of HD (HD monkey) shows neuropathological, behavioral and molecular changes similar to an HD patient. Additionally, neural progenitor cell (NPC) derived from HD monkeys can be maintained in culture and differentiated to neural cells with distinct HD cellular phenotypes including the formation of mHTT aggregates, intranuclear inclusions and increased susceptibility to oxidative stress. Here, we evaluated the potential application of HD monkey NPCs (HD-NPCs) and neural cells (HD-NCs) as an in vitro model for HD drug discovery research.

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Production of Transgenic Nonhuman Primates

Cited by 4 publications

References 353 publications

Pathogenic Cellular Phenotypes are Germline Transmissible in a Transgenic Primate Model of Huntington's Disease

Pathogenic Cellular Phenotypes are Germline Transmissible in a Transgenic Primate Model of Huntington's Disease

Transgenic Animal Models of Neurodegenerative Diseases

Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

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