Down syndrome (DS) causes such a complex set of abnormalities in the developing nervous system that the resulting mental disabilities of people with DS have been considered untreatable. But researchers have created strains of mice that mimic DS’s genetic abnormalities, and have begun to show that existing drugs can successfully treat specific kinds of cognitive deficit in these mice. A study published on June 30 in the Journal of Neuroscience, for example, indicates that Prozac (fluoxetine), delivered to these mice shortly after birth, reverses a key brain abnormality and enables the mice to perform a standard memory test as well as normal mice.
“Based on all our data we think that fluoxetine is a good candidate for clinical trials,” says Renata Bartesaghi of the University of Bologna, senior author of the study.
“I think the field is wide open now and really ripe for major discoveries,” says Alberto Costa of the University of Colorado–Denver Medical School, whose lab has shown similar results for the cognitive-boosting drug memantine, and is now conducting a clinical trial of the drug in young people with DS.
In humans, DS typically begins with a mistake in the formation of an egg cell that leaves it—and any embryo resulting from the fertilization of that egg—with an extra copy of chromosome 21. A segment of the mouse chromosome 16 is very similar to human chromosome 21, so mice engineered to have an extra copy of this segment—known as Ts65Dn mice—are considered a potentially useful model of the human disease, despite the obviously incomplete similarity between mice and humans.
In Ts65Dn mice as well as in humans with DS, researchers previously have noted a relative lack of neurogenesis, or production of new neurons, which is crucial for normal brain development. Some antidepressant drugs such as fluoxetine are known to promote neurogenesis, so Bartesaghi and her colleagues dosed their Ts65Dn mice with fluoexetine from day 3 to day 15 after birth, and then compared them to a group of untreated Ts65Dn mice.
The treated mice seemed vastly improved. They showed normal or even higher-than-normal levels of neurogenesis at day 15 and day 45, whereas untreated Ts65Dn mice showed much lower than normal levels. The treated Ts65Dn mice also regained a normal number of cells in a part of a crucial memory region, the hippocampus, where neurogenesis is particularly intense and persists into adulthood in humans. In a test of the memory of a specific place—a memory strongly dependent on the hippocampus—the treated Ts65Dn mice also performed as well as genetically normal mice. By contrast, the untreated Ts65Dn mice scored poorly on all measures.
The study appears to confirm and extend a study published in 2006 by a group of researchers including Costa, who found similar improvements in neurogenesis for fluoxetine-treated Ts65Dn mice—but adult mice, not newborns. “It’s always nice to see some of your own findings being replicated,” says Costa. “And on top of that they did experiments we hadn’t done.”
Costa abandoned fluoxetine as a candidate because despite their recovery of neurogenesis, his treated Ts65Dn mice failed to show improvement on a key memory test then commonly used – a variant of what is known as the Morris water maze. The behavioral improvements in newborn Ts65Dn mice reported by Bartesaghi’s group make him more optimistic about the drug, however. “I find their results interesting and impressive,” he says. “I definitely would include fluoxetine as a candidate for clinical trials in the future.”
The Bartesaghi group emphasizes treatment at the start of life, not in adulthood, in order to correct abnormalities in brain development at the earliest possible stage. But early treatment poses a special challenge in humans: Neurogenesis in most parts of the brain, including the cortex, which mediates higher, distinctively “human” functions, is largely completed during the fetal stage of life.
Bartesaghi says that her group therefore has begun treatment on Ts65Dn mice when they are still in the womb, to see if the growth of the cortex, which is much reduced in people with DS, can be somewhat restored. “From our preliminary data it appears that prenatal treatment is extremely effective and does not have aversive effects on the pups,” she says.
High hopes and caveats
In 2008, Costa’s group reported that memantine, a drug currently approved for treating symptoms of Alzheimer’s disease, restored the performance of grown Ts65Dn mice on a memory test similar to the one used by Bartesaghi’s group. Memantine has the effect of moderately reducing the activity of NMDA receptors on brain cells – activity that appears to be abnormally high in Ts65Dn mice. But Costa doesn’t yet know precisely how memantine’s effects on NMDA receptors translates into cognitive improvements in the mice. Memantine does appear to be a relatively safe drug, however, and Costa recently was able to begin enrolling 40 adolescents and young adults with DS in an initial 16-week clinical trial, which he expects to conclude late this year or early in 2011. More than 400,000 people in the United States have DS, according to the National Down Syndrome Society.
Even though his DS subjects are nearly full-grown, Costa hopes that the study will show some hints of cognitive improvement. But he doesn’t expect a miracle. “Nothing’s going to happen in the four months of our trial that will change daily living skills for those individuals,” he says. “Those take a long time even in a normally developing person.” Much larger and longer trials would be necessary to prove memantine’s efficacy in any case, Costa adds.
Frances Wiseman, a DS researcher at University College, London, also cautions that, so far, these mouse tests have been done with relatively narrow measures of cognitive performance. In the case of fluoxetine, she says, “it would be sensible to repeat the treatment with a wider range of behavioral tests, and perhaps in another mouse model of Down syndrome, before embarking on a clinical trial.”
Both she and Costa note that although fluoxetine is now routinely prescribed for children as an antidepressant, an apparently above-normal incidence of suicidal ideation in young users has made its use in this age group somewhat controversial. Wiseman points out too that in at least one case reported in the early 1990s, fluoxetine was associated with seizures in a patient with DS.
Lithium, another mood-stabilizing drug that has the effect of promoting neurogenesis, is also being tested in adults with DS in a clinical trial at King’s College, London. Bartesaghi and her colleagues reported earlier this year on a successful test of lithium in Ts65Dn mice. But Bartesaghi doesn’t think lithium is a good candidate for use in children or infants with DS, because it is considered too toxic in that age group; in her lab, newborn Ts65Dn mice given the drug had a high mortality rate.
“One has to be aware of all the caveats,” says Costa. “But on the whole I’m now very optimistic about the prospects for treating Down syndrome, otherwise I wouldn’t have started a clinical trial. The field has long been neglected, but it’s now definitely getting interesting.”