Basmisanil

The genetic basis for Down syndrome in humans, also known as trisomy 21, is a third copy of chromosome 21. The road to developing therapies for the cognitive impairments seen in Down syndrome is paved with preclinical successes and clinical failures. But upgrading to a new, more accurate mouse model could change that. In a study published March 14 in Biological Psychiatry, researchers from the U.S. National Institutes of Health (NIH) described the development of a new mouse model that’s genetically more similar to humans with Down syndrome than the existing “gold standard” model. Despite some limitations, its use could help researchers make better predictions about what drugs will work in patients. "Our goal was to find the best mouse model that we could use for our long term goal of developing and assessing treatments that pregnant women can take to improve brain development and neurocognition in fetuses that have been diagnosed with [Down syndrome],” first author Faycal Guedj, Ph.D. and senior author Diana Bianchi, M.D., director of the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, told Fierce Biotech Research in an email. “It was important for us to have a mouse model that demonstrated atypical neurodevelopment during embryonic life.” The genetic basis for Down syndrome in humans, also known as trisomy 21, is a third copy of chromosome 21. That third chromosome leads to triplicates of more than 200 genes, which in turn results in intellectual, speech and motor disabilities, along with a near-guarantee that the individual will develop Alzheimer’s disease. While mice have only 20 pairs of chromosomes, their genes are similar enough to ours that it’s possible to create extra copies of the same genes affected in humans with Down syndrome by replicating their chromosomes 10, 16 and 17. That’s what scientists did to create the gold standard model, Ts65Dn, which has been used in Down syndrome research since at least 1995. But mice have genes on chromosome 17 that aren’t found on human chromosome 21—45 of them, in fact. Before the Bianchi lab's study, it wasn’t clear exactly what those genes did or how they might be contributing to the disabilities seen in the Ts65Dn mouse model. To find out, the team used a model developed by researchers from the University of Strasbourg in France, who used CRISPR to remove the 45 extra genes from Ts65Dn mice. This created a new strain, Ts66Yah. The Bianchi lab then compared Ts66Yah with Ts65Dn to see how their disabilities matched up. They were surprised to find that the new model had much milder impairments. “We were expecting that the Ts66Yah model would exhibit a less severe phenotype than the Ts65Dn but not to the extent we saw it in this study,” the researchers said. The results could help explain why only one pharmaceutical intervention for Down syndrome has shown to improve cognition in patients (and even then, only in a small pilot study). Perhaps the most striking failure in the past decade is Roche’s drug basmisanil, which modulated signaling by the neurotransmitter GABA. The company scrapped a phase 2 clinical trial of the drug in teens and adults with Down syndrome when it failed to improve their cognitive functioning—a disappointing finding after studies on the Ts65Dn mouse model had suggested GABA signaling would be a promising target. Though the drug likely did improve cognition in the mice, it may have been doing so through a mechanism involving genes that aren’t relevant to people. “In humans with Down syndrome,” the researchers explained, “there is no evidence that GABA signaling is increased.” The new mice have their own drawbacks. Only half of the genes that are triplicated in Down syndrome are triplicated in the new model, and its relatively milder cognitive deficits may make it more challenging to evaluate whether the therapies are effective or not, the researchers explained. Plus, of course, they’re not yet widely available. Still, given that the extra genes were causing noticeable effects on the brain development and behavior of the Ts65Dn model, the new one is more precise, the researchers said. Bianchi’s lab is now working with human stem cells to understand the differences in gene and protein expression between people with Down syndrome and those who have typical pairs of chromosomes, which will help with drug selection. The team will then turn to the new model to see how the mice respond to treatment. As for the Ts65Dn model? It still has a place in the lab. The large body of research already done on it makes it useful for testing future mouse models, the researchers said. “It also may be useful to examine the role of individual triplicated genes that are coming from mouse chromosome 17 and their potential role in normal brain development,” they added. Editor's note: This article has been updated to clarify that the quotes provided were supplied by both researchers and that the mouse model was developed by the University of Strasbourg researchers, while the studies were conducted by Bianchi's lab at the NHGRI. We have also added that mouse chromosome 10 is triplicated in mouse models of Down syndrome.