In the first study of its kind, researchers at the Yerkes National Primate Research Center, Emory University, in collaboration with researchers from the Department of Human Genetics at Emory's School of Medicine, have developed the first transgenic nonhuman primate model of Huntington's disease (HD), one of the most devastating human neurodegenerative diseases.
This development, reported in the May 18 Advance Online Publication of Nature, is expected to lead to greater understanding of the underlying biology of HD and to the development of potential therapies. In addition, this pioneering study, which was supported by a grant from the National Institutes of Health, is leading the way toward the development of nonhuman primate models of other genetic diseases.
HD is a genetic, neurodegenerative disorder that causes uncontrolled movements, loss of mental processing capabilities and emotional disturbances. Patients succumb to the disease within 10 to 15 years of the onset of the symptoms.
According to lead researcher Anthony W.S. Chan, DVM, PhD, "In the past, researchers have used transgenic mouse models to study the disease. These models do not completely parallel the brain changes and behavioral features observed in humans with HD, thus making the development of a transgenic nonhuman primate model critical to currently treating and ultimately preventing the disease."
Chan, an assistant research professor at the Yerkes Research Center and an assistant professor in the Department of Human Genetics, and his research team (Yerkes: J. Bachevalier, Y. Smith, S. Zola; and Department of Human Genetics: SH Li, XJ Li), produced the HD transgenic rhesus macaques by:
- Injecting130 mature oocytes with:
- a lentivirus expressing the mutant htt gene with expanded polyglutamine repeats, which is the primary cause of HD, and
- a lentivirus expressing a green fluorescent protein (GFP) gene;
- Fertilizing the oocytes by intracytoplasmic sperm injection (ICSI); and
- Transferring 30 embryos into eight surrogates.
- This resulted in six pregnancies and five live births (two sets of twins and one singleton); all carried the mutant htt and GFP genes. Two continue to survive.
Chan noted, "The transgenic monkeys are providing us with unparalleled opportunities for behavioral and cognitive assessments that mirror the assessments used with humans. With such information, much of which we are obtaining by using the Yerkes Research Center's extensive imaging capabilities, we are developing a more comprehensive view of the disease than currently available."
Chan's research team is one of several at Yerkes focused on the genetic basis of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases.
"This study is a complement to the many neuroscience programs at Yerkes and further solidifies our role at the forefront of neuroscience research," said Stuart Zola, PhD, director of the Yerkes Research Center and the study's co-investigator leading the behavioral assessments. "Access to Emory's department of human genetics, our collaborations with the department of neurology, our own imaging center and, of course, our animal colony make Yerkes one of the few places in the world where this type of study can be done," Zola continued.
The researchers, who are continuing to monitor and assess the transgenic monkeys, believe their progress bodes well for developing transgenic nonhuman primate models of other neurodegenerative diseases, such as Alzheimer's. "The development of all such models is invaluable for understanding disease pathogenesis and for developing early diagnostic and treatment strategies," Zola continued.
For more than seven decades, the Yerkes National Primate Research Center, Emory University, has been dedicated to conducting essential basic science and translational research to advance scientific understanding and to improve the health and well-being of humans and nonhuman primates. Today, the center, as one of only eight National Institutes of HealthÐfunded national primate research centers, provides leadership, training and resources to foster scientific creativity, collaboration and discoveries. Yerkes-based research is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate, quality animal care.
Within the fields of microbiology and immunology, neuroscience, psychobiology and sensory-motor systems, the center's research programs are seeking ways to: develop vaccines for infectious and noninfectious diseases, such as AIDS and Alzheimer's disease; treat cocaine addiction; interpret brain activity through imaging; increase understanding of progressive illnesses such as Parkinson's and Alzheimer's; unlock the secrets of memory; determine behavioral effects of hormone replacement therapy; address vision disorders; and advance knowledge about the evolutionary links between biology and behavior.
In addition to Chan(1,2,4,5), study authors were: Shang-Hsun Yang(1,2,4), Pei-Hsun Cheng(1,2), Heather Banta1, Karolina Piotrowska-Nitsche(1,2,9), Jin-Jing Yang(1,2), Eric C.H. Cheng(1,2), Brooke Snyder(1,2) , Katherine Larkin(1), Jun Liu(1,2,5), Jack Orkin(1), Zhihui Fang(2), Yoland Smith(1,5,6), Jocelyne Bachevalier(1,3,7), Stuart M. Zola(1,5,7,8), Shihua Li(2) and Xiao-Jiang Li(2, 4,5).
1 Yerkes National Primate Research Center, 2 Department of Human Genetics, Emory University School of Medicine, 3 Department of Psychology, Emory University, 4 Genetics and Molecular Biology Program, Emory University School of Medicine, 5 Neuroscience Program, Emory University School of Medicine, 6 Department of Neurology, Emory University School of Medicine, 7 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 8 Veterans Affairs Medical Center, Atlanta, Georgia, 9 Department of Experimental Embryology, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, 05-552 Wolka-Kosowska, Poland
The National Institutes of Health provided funding for this study. In addition, the National Center for Research Resources, via a base grant to the Yerkes Research Center, supported this study.
Reference: "Toward a transgenic model of Huntington's disease in the nonhuman primate," Nature, Advance Online Publication, May 18, 2008.
Anthony Chan, DVM, PhD
Since 2002, Chan has been an assistant research professor in the Division of Neuroscience at the Yerkes National Primate Research Center and an assistant professor in the Department of Human Genetics at Emory University School of Medicine. He is known for producing ANDi, the first genetically modified monkey. ANDi carried the jellyfish gene for green fluorescent protein.
Yerkes National Primate Research Center:
Jocelyne Bachevalier, Division of Psychobiology
Yoland Smith, Division of Neuroscience
Stuart Zola, Director
Department of Human Genetics at the School of Medicine:
Huntington's disease is an inherited genetic neurodegenerative disorder. It affects five to 10 people in every 100,000. Symptoms include mood swings, depression, irritability and difficulty learning new things, remembering facts and/or making decisions. Generally, the first symptom noticed is involuntary limb movements. Death typically occurs 10 to 15 years after onset. There is no treatment to halt progression of the disease, only medications to relieve symptoms.
Transgenic animals are created using a recombinant DNA method to deliberately modify a genome. To modify the genome, researchers introduce foreign DNA into oocytes or early embryos.
The lentiviruses used in this study were non-infectious and replication incompetent. This viral vector has been widely used in biomedical research, including gene therapy.
Green Fluorescent Protein (GFP)
GFP is a protein originally isolated from jellyfish that fluoresces green when exposed to blue light.
A genetic character arising or resulting from the change within the DNA of a gene.
This is a functional unit that composes all the components necessary for expressing a gene of interest in bacteria, yeast or mammalian cells.
A protein that is produced based on the genetic code of a gene.
The observable expression of a genotype as a morphological, clinical, biochemical or molecular process. A phenotype may be either normal or abnormal in a given individual.
A quantitative method that allows researchers to determine the progression of the disease.
A serial of studies in parallel with the development of disease.