21 May 2008. Scientists at the Yerkes National Primate Research Center in Atlanta, Georgia, have developed a primate model of Huntington disease. Researchers led by Anthony Chan claim that “a transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies.” The research is published in the May 18 Nature online.
Joint first authors Shang-Hsun Yang, Pei-Hsun Cheng, and Heather Banta used lentiviruses to infect 108 rhesus macaque oocytes with a vector carrying a mutated human huntingtin gene with 84 polyglutamine-encoding CAG repeats. After fertilizing the eggs by injecting them with sperm, 89 of the eggs developed to the four- to eight-cell stage. The researchers transferred 30 embryos into eight surrogate mothers, and five newborns were delivered at full term. One monkey seems suitable for studying HD. Two survived less than one day and one survived for only one month, with severe chorea, dystonia, and difficulty swallowing. Though it is unclear why these animals did not survive, the level of mutant huntingtin in placental tissue correlated with length of survival—animals that died earliest had the most intense staining with the mEM48 antibody that recognizes polyglutamine-expanded huntingtin. Of the two monkeys that survived (they were six months old when the manuscript was written), one has 29 polyglutamine repeats, which is within the normal range for humans, and appears to be a normal monkey. The other monkey has 83 repeats and, at six months old, showed some signs of HD including dystonia and chorea. Postmortem analysis of the dead primates showed extensive aggregates of huntingtin in the cortex and striatum.
Huntington disease is a progressive, fatal neurodegenerative disorder. Though the genetic basis for the disease was first uncovered in the early 1990s, there has been little progress in finding a cure. In an accompanying News & Views article, Stéphane Palfi and Bechir Jarraya at the Assistance Publique-Hôpitaux de Paris write that this research “takes us another step on the long road towards developing a treatment for Huntington’s disease,” but add, “we must retain a healthy caution, as there is a need to determine how closely the characteristics of these authors’ transgenic monkeys match the spectrum of symptoms of Huntington’s disease.”
This is the first time researchers have used large-animal transgenics to induce a fatal neurodegenerative disease in primates. The paper notes that all procedures were approved by the Yerkes National Primate Center and Emory Animal Care and Biosafety Committees. In the general media, this study received widespread coverage, most of it sidestepping any potential questions about the ethics of such research. One news article, in the online Daily Telegraph, U.K, noted that the Royal Society for the Prevention of Cruelty to Animals was critical of the work.—Tom Fagan.
Yang S-H, Cheng P-H, Banta H, Piotrowska-Nitsche K, Yang J-J, Cheng ECH, Snyder B, Larkin K, Liu J, Orkin J, Fang Z-H, Smith Y, Bachevalier J, Zola SM, Li S-H, Li X-J, Chan AWS. Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 2008, May 18. Advanced online publication. Abstract
Palfi S, Jarraya B. Huntington's disease: Genetics lends a hand. Nature. 2008 May 18. Abstract