Scientists at the Yerkes National Primate Center in Atlanta have reported the development of genetically engineered monkeys that carry the mutant gene for Huntington’s disease. The work represents a major development in preclinical research, especially as applied to neurodegenerative diseases—for which transgenic monkeys should make much more accurate models than transgenic mice.
“We’ve seen Huntington’s-type clinical features in our monkeys that haven’t been observed in other models” of the disease, says Anthony Chan, whose laboratory published the work online in Nature on May 18.
Chan and his colleagues made their “Huntington’s monkeys” by combining test tube fertilization with a special gene-transfer method. They used an HIV-like viral “vector” to deliver the human Huntington’s-causing gene, known as HTT, into the DNA of the eggs prior to fertilization. The vector also included a gene coding for GFP, a fluorescent protein that emits green light, thus enabling the researchers to see whether the transgenes were active. (Chan and his colleagues reported making the first, proof-of-principle transgenic monkeys in 2001, with a simple GFP-only transgene.)
With the several dozen HTT-positive embryos created, the researchers established six pregnancies, of which three resulted in full-term live births—including two pairs of twins—making five monkeys in all. Three monkeys carried multiple copies of mutant HTT and, seemingly as a result of this extra-strong disease promotion, died soon after birth. Two of these three died at the age of one day, and the third died at one month, with movement abnormalities and breathing difficulties strikingly reminiscent of human Huntington’s.
Two other monkeys carried a single copy of HTT and remain alive, although their health—as for humans—differs according to the form of HTT each carries. HTT normally contains a three-nucleotide sequence, CAG, that codes for the amino acid glutamine and is repeated a number of times, thus coding for a chain of amino acids called polyglutamine. Fewer than 36 glutamine segments is normal, 36 to 39 is a “gray area” in which disease may or may not appear, and 40 or more is so toxic that even with one such copy of HTT a person would be expected to develop Huntington’s if he or she lives long enough—and in general, the longer the polyglutamine chain the earlier the disease will appear.
One of the still-living monkeys carries a single copy of HTT but with only 29 glutamine segments; that monkey appears normal and healthy. The other carries 83 glutamine segments and consequently fell sick very early, displaying Huntington’s-like movement disorders from the age of one week.
Since reporting their initial results, Chan and his colleagues continue to follow these two monkeys to watch how disease unfolds in the sick one and whether it appears at all in the healthy one. Chan says he suspects that the ideal “Huntington’s monkey” will have a mutation whose disease-driving power lies in between these two cases, causing disease but in the more gradual way seen in human Huntington’s cases. “The next step for us is to generate a monkey that has a later disease onset, so it is at least three or four years old when the disease begins to develop,” he says.
“The [transgenic Huntington’s monkey] paper is still very early in the story; it’s almost like a progress report,” says John Morrison, a neurodegenerative disease researcher at Mount Sinai School of Medicine in New York. “But it was important to get it out there, because now you’ve got pathology that really starts to look like what you see in humans. And you have the choreaform movements, and the cognitive problems that you see in humans. Those don’t appear in the mouse model of Huntington’s disease.”
Morrison, who has worked extensively with both mouse models and non-transgenic monkey models of neurodegenerative diseases such as Alzheimer’s, suggests that funding agencies should shift greater resources towards monkeys, even though the cost of keeping a lab monkey alive long enough to observe disease—and its response to a prospective therapy—is at least several times higher than that for a mouse.
Chan agrees: “I don’t know that even 1,000 mice can tell us the same thing that a monkey can tell us.”