Emory University researchers announced in the May 18 Advance Online Publication of the journal Nature that they have developed the first transgenic nonhuman primate model of Huntington's disease. Researchers at the Yerkes National Primate Research Center at Emory University worked in collaboration with researchers from the Department of Human Genetics at Emory's School of Medicine to develop the new model.

The goal is to have an animal model of the disease that more closely captures the symptoms of human Huntington’s Disease. 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."

Walter Koroshetz, M.D., deputy director of the NINDS, agreed. "Genetic advances make it easy to identify who has inherited the disease gene. Now, with a primate model of Huntington’s disease, we are one large step closer to finding better treatments for people with the disease as well as those destined to develop it."

Dr. Chan, an assistant research professor at the Yerkes Research Center and an assistant professor in the Department of Human Genetics, and his research team produced the HD transgenic rhesus macaques by injecting 130 mature eggs with a lentivirus which expressed exon 1 of the human HD gene with 84 CAG repeats. The eggs were fertilized and 30 embryos were transferred into eight surrogates. This resulted in six pregnancies and five live births (two sets of twins and a single birth).

The repeat lengths varied in the animals. One was born with 29 repeats and remained healthy at six months when the report was written. The other four had higher repeats and were either symptomatic at birth or within a week. A second monkey with 83 repeats developed mild motor symptoms within a week. He remains alive with symptoms of chorea, dystonic, and respiratory difficulties. A third monkey with 84 repeats lived for a month and showed severe symptoms of chorea, dystonia, dysphagia (problems swallowing), and respiratory difficulties. The fourth monkey had repeats varying from 27 to 65 and died within a day as did the fifth who had repeats of 88. Both had severe respiratory problems and showed signs of movement impairment. The brains of the fourth and fifth monkey were examined and HD protein aggregates were found in the striatum and cortex.

The researchers are studying the two surviving monkeys. 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."

Like all models, this one has its limitations. As with the R6/2 mice, these animals were given a fragment of the human protein with a large number of repeats and can be expected to get sick very quickly. This makes it difficult to study preclinical development of the disease, especially the role of the fragmentation of the protein in disease progression – the toxic fragment theory associated with the work of Dr. Michael Hayden -- or to test early interventions into the disease.

However, the researchers have established a proof of principle that a primate model can be created and will be doing more work to establish a group of research monkeys for further research. According to Dr. Chan’s faculty page, one such treatment that he would like to study in the monkeys is embryonic stem cell transplantation.

While a primate model will certainly yield more insights about the disease, its greatest contribution may turn out to be its use in the preclinical testing of potential treatments with higher risks, such as ESC transplantation or various genetic interventions. I think it's unlikely that the FDA would approve clinical trials for those types of interventions without primate studies.