Researchers often rely on mice to study a host of genetic diseases in the lab. That's not a satisfactory approach for many neurodegenerative illnesses, which involve cognitive and behavioral symptoms that don't map easily from human patients onto rodents. Now, in a development that opens the door to modeling such illnesses in primates, researchers have created the first transgenic monkeys with neurological signs of Huntington's disease (HD).
HD is caused by a mutation to a gene called HTT that triggers the degeneration of neurons in the striatum and the cortex, leading to involuntary muscle movements and mental difficulties. Anthony Chan, a geneticist at Emory University's Yerkes National Primate Research Center in Atlanta, Georgia, and his colleagues injected the mutant HTT gene into 130 oocytes taken from rhesus macaque monkeys before fertilizing them in the lab. They implanted 30 of these embryos into eight female macaques. In the end, five took hold and survived delivery, producing the newborn macaques described online today in Nature.
Two monkeys whose tissues showed high expression of the mutant gene suffered from breathing difficulties and other motor impairments. They died within a day after birth. In their brain tissue, the researchers saw evidence of neuronal damage similar to that seen in Huntington's patients. Another newborn monkey started to display involuntary movements a week after birth and died within a month. Of the remaining two monkeys, which were 6 months old at the time the authors submitted the paper, the mutant gene was minimally expressed in one and at a moderate level in the other: The first behaved normally whereas the second showed classic HD symptoms such as jerky limb movements and twisted posture.
Chan and his colleagues are now following these two animals, using brain imaging and cognitive behavioral tests to study the progression of the disease. "We believe integrating the information from these studies will allow us to better understand how HD develops and progresses," Chan says.
The technological feat of designing transgenic primates with a disease-carrying gene is "a tremendous advance," says Christopher Ross, a neuropsychiatrist at Johns Hopkins University in Baltimore, Maryland. "The monkey phenotype looks very similar behaviorally to the human phenotype," which should make the primates better than mice for testing Huntington's drugs, says Ross. The great hope, he says, is that the technique will one day lead to primate models of "schizophrenia and other neuropsychiatric diseases that are not easily modeled in mice." Before then, of course, researchers will have to sort out the complex genetic contributions to those disorders.