Contents

Message

CTSAs In Focus

Critical Resources

Funding Matters

News from NCRR

Science Advances

New Opportunity to Better Understand Huntington's Disease

New primate model may help scientists to develop more effective therapies for Huntington's disease and create similar primate models for other genetic disorders.
By Karen Eddleman

Although strides have been made in understanding neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases, a lack of useful animal models has stood in the way of advancing research that might lead to effective treatments or cures. Now — for the first time ever — a team of researchers has successfully introduced a gene for a human disease into a primate, creating an animal model that shows disease progression and symptoms characteristic of human Huntington's disease, an incurable and inherited genetic disorder affecting the brain. This advance was achieved by a team of scientists led by Anthony W.S. Chan, principal investigator, at the NCRR-supported Yerkes National Primate Research Center (NPRC), Emory University, one of eight primate research centers supported by NCRR. Chan and his colleagues hope the new animal model will herald a new age in Huntington's disease research and ultimately help lead to a cure.

As reported in the journal Nature (453:921–924, 2008), Chan's team introduced a gene that can cause Huntington's disease in humans (an altered form of the gene HTT) into the germline DNA of a rhesus macaque monkey (Macaca mulatta), resulting in what is termed a transgenic animal model. Although scientists identified the precise location of the HTT gene 15 years ago and have engineered rodents and other animals to carry the altered HTT gene, research has been hampered because these models do not experience the same brain and behavioral changes as observed in humans.

Huntington's disease occurs in one of every 10,000 persons — nearly 30,000 in the United States — and about 150,000 more are at risk of inheriting the disease from a parent. It causes uncontrolled movements and stumbling, short-term memory loss, depression, mood changes, and sometimes aggressive or antisocial behavior. The disease inevitably leads to death 15 to 20 years after symptoms appear, usually in middle age. It is one of several diseases caused by abnormal repetition within the DNA of the HTT gene, which codes for a protein called huntingtin. The modified form of the huntingtin protein contains a section with extra glutamine amino acids; it causes cells to die in certain areas of the brain, affecting neurological functions. Currently, there is no treatment to delay or prevent Huntington's disease.

Now, research into Huntington's disease has been jumpstarted by Chan's work, which was supported by NCRR and the National Institute of Neurological Disorders and Stroke. Because the transgenic macaque model developed at the Yerkes NPRC shows many of the symptoms and the disease progression seen in humans with Huntington's disease, it offers the possibility of testing innovative therapies intended to ameliorate disabling symptoms and perhaps extend the lives of Huntington's patients.

In 2001, Chan, while working at the NCRR-funded Oregon NPRC, successfully introduced a jellyfish gene for green fluorescent protein (GFP), creating the world's first transgenic nonhuman primate. According to Chan, "The next step was to try to insert a human gene that causes disease."

In 2002, Chan joined the team at the Yerkes NPRC, where studies of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are a main focus. "Dr. Chan is one of the very few investigators who could do this work. He has experience in manipulating monkey embryos," says John Harding, director of primate research at NCRR. Chan's research is critical, in his view, "because rodent models cannot give the answers we need; we have to rely on nonhuman primates, which are physiologically very similar to humans."

The study team developed this transgenic monkey model by introducing a genetically altered human HTT gene as well as the jellyfish GFP gene (used as a marker to show that gene transfer has been achieved) into monkey eggs using a viral vector. The eggs were fertilized, and the resulting embryos were introduced into surrogate mothers, resulting in five live births. All of the monkeys were shown to have the modified human HTT gene incorporated into the DNA of all of their cells, and three expressed very high levels of the mutant huntingtin protein.

The Yerkes NPRC was the ideal setting for this work. NCRR's eight NPRCs together have more than 26,000 animals representing more than 20 species of nonhuman primates, mostly macaques. Research studies at these facilities are tackling questions about human health and disease that cannot be assessed ethically in humans or answered in other species. "The Yerkes NPRC is one of the few places in the world where scientists can find expertise in neurobiology and nonhuman primate transgenesis, noninvasive imaging technology, husbandry, and behavioral and cognitive assessment tools in one place," says Harding. Equally important as the infrastructure made available through NCRR’s support, according to Stuart M. Zola, director of the Yerkes NPRC, was NCRR’s recognition that “the research was high risk, but it offered a potentially high payoff. NCRR was willing to take that risk.”

According to Chan, the Hereditary Disease Foundation and several other Huntington’s disease advocacy groups have expressed optimism about the prospect that these animal models can help science take the next steps toward a cure for Huntington’s disease.

Future efforts by Chan and colleagues at Yerkes NPRC will be directed along several different paths. First, more tests need to be conducted to validate the nonhuman primate model of Huntington’s disease. The transgenic monkeys will undergo cognitive testing and continued blood sampling to monitor their genomic and metabolic profiles and gene expression patterns. The study team will use the Yerkes NPRC’s facilities to conduct noninvasive magnetic resonance imaging studies to follow any anatomical changes. “We will integrate all these studies into a picture of the disease and validate the animal models by comparing the results with information on human pathology and clinical features of Huntington’s disease,” explains Chan. Having a validated model will be a key step before scientists can confidently proceed to using the animals for developing and testing possible therapies.

Because the disease seems to be progressing rapidly in the two animals currently under study, Chan plans to develop additional transgenic models with later onset of disease. Having more transgenic monkeys available will allow translational research aimed toward potential cures to progress more quickly, says Chan. Zola foresees using transgenic primate models for studying other important diseases: “One barrier in terms of neurodegenerative diseases is the lack of adequate animal models.

Zola foresees using transgenic primate models for studying other important diseases: “One barrier in terms of neurodegenerative diseases is the lack of adequate animal models. For example, no other species develops Alzheimer’s disease; therefore, it is hard to explore the dynamics and underpinnings of the disease, its stages, and how we might be able to intervene effectively,” he says. “This transgenic approach in nonhuman primates is exciting, because the models show the full spectrum of the disease so we can better develop and assess interventions.”

The research described in this article is supported in part by grants to the Yerkes NPRC, one of eight NCRR-funded primate research centers nationwide, and by grants awarded to several of the investigators by the National Institute of Neurological Disorders and Stroke.