New $11 million award to study intellectual disability in Down syndrome

Waisman investigators Anita Bhattacharyya, PhD, an assistant professor of cell and regenerative biology and Su-Chun Zhang, MD, PhD, professor of neuroscience and neurology at the School of Medicine and Public Health at UW-Madison, were awarded an $11 million Transformative Research grant by the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) to study developmental brain changes that lead to intellectual disability in Down syndrome. Part of the High-Risk, High-Reward Research program, the NIH Director’s Transformative Research Award supports exceptionally innovative or unconventional research projects with the potential to create or overturn fundamental paradigms.

Down syndrome, also known as trisomy 21 (T21) due to the triplication of chromosome 21, is the most common genetic cause of intellectual disability, affecting approximately 6 million people worldwide. Bhattacharyya, Zhang, and two other Waisman researchers are combining efforts to develop models that will allow for the study of disruptions in brain development that result in cognitive dysfunction in Down syndrome. The study may reveal how brain development in individuals with Down syndrome differs from typically developing individuals, identify features that will help understand intellectual disability in Down syndrome, and identify potential targets for therapy.

“One of the things that I was really acutely aware of is that, although Down syndrome is quite prevalent and we know a lot about individuals with Down syndrome —their characteristics, their features, we even know that they will develop Alzheimer’s disease—what we don’t have a good understanding of is how brain development in Down syndrome is different. We have surprisingly little information about this,” says Bhattacharyya.

Current animal models used to study the syndrome, Bhattacharyya says, fail to mimic the disorder well. Bhattacharyya’s proposed model will be based on human induced pluripotent stem cells (iPSCs), a type of stem cell derived from adult skin or blood cells that can be reprogrammed to become other functional cell types, such as neurons, a type of brain cells. Using iPSCs derived from individuals with Down syndrome and transforming them into neurons from the cerebral cortex –a part of the brain that makes humans, humans, Bhattacharyya explains – they can accurately study which neuronal pathways are affected by T21 during development.

In order to have a reference that validates their stem cell-based model, they plan to build an atlas of the prenatal cortex in Down syndrome. For this atlas, they will identify the specific types of neurons, synapses and molecular pathways that are altered in Down syndrome, particularly during prenatal-to-early postnatal stages. “The atlas will give us a roadmap of what happens in prenatal brain development in Down syndrome,” says Bhattacharyya.

After determining these changes, they will use the iPSCs derived from individuals with Down syndrome to figure out if the stem cells mimic those differences observed in the prenatal brain. “The model is only good if it recapitulates or mimics what’s really happening,” says Bhattacharyya.

In addition, Zhang’s lab will decipher the functional differences in T21 neurons. Previous data from Zhang and Bhattacharyya indicate that human T21 neurons are not as active as their control counterparts. This study will extend these findings by digging deep into the causes of this reduced activity. The causes of intellectual disabilities in Down syndrome are prenatal, which creates a challenge because of the limited access to prenatal brains.
Bhattacharyya hopes that by directly comparing their stem cells to prenatal tissue, they will be able to validate the stem cells and confidently move forward with them as a model.

So far, their results show that these iPSC-derived cells recapitulate some of the changes, such as missing neuron types, observed in adult brains of individuals with Down syndrome. These results give them confidence that their model will present more of these features.

“This is my dream project,” says Bhattacharyya, “and it took 15 years to get it together because several things had to happen. One is, we had to assemble the right people to do this kind of project.”

The work will be done in collaboration with new Waisman Center investigators Daifeng Wang, PhD, assistant professor of biostatistics and medical informatics, and computer science, and André Sousa, PhD, assistant professor of neuroscience.

“We have assembled this amazing team that all happen to be at Waisman Center,” says Bhattacharyya. “Zhang, who is known for using human stem cells to study neurodevelopment and neurodegenerative disorders, my lab that is focused on Down syndrome modeling, Sousa, who has expertise in single-cell sequencing in human brain development, and Wang, who is going to take all that data and apply his computational skills.”

This five-year grant, which also includes collaborators at the University of Washington-Seattle and Seattle Children’s Hospital, will allow the team to explore an understudied yet needed area of Down syndrome research, which they hope will help inform more research on Down syndrome in the future, for their lab and others.

This research was supported by a grant from the National Institute for Child Health and Human Development 1R01HD106197-01.