So McClure-Begley and his colleagues took a fibroblast from a single Down syndrome patient, coaxed it into becoming two iPSC lines, and then reprogrammed those cells into neural progenitor cells that self-organized into cerebral tissue in vitro. “So we get a window into what an individual central nervous system development looked like from a cellular and molecular level,” he said during a Monday (October 19) press conference at the Society for Neuroscience (SfN) annual meeting held in Chicago.
The researchers found that protein expression did not follow a simple 1:1 ratio with the extra genes on the triplicate chromosome 21 leading to a proportional increase in proteins expressed. “Rather, there’s a complex change, where some proteins are upregulated, some proteins are downregulated—all reflecting a general disturbance in signaling,” McClure-Begley said. Many of the perturbed proteins were involved in early neurogenesis and cell cycle regulation, among other functions.
Earlier this year, researchers in Germany reported similar success growing cerebral organoids from iPSCs derived from skin cells of people with autism.
McClure-Begley added that his group plans to generate as many organoids from Down syndrome patients as possible in order characterize protein-expression profiles across the spectrum of the disorder, from mild to severe. “We can start observing . . . the discrete factors in their genome not on chromosome 21 that can influence the severity of their clinical presentation of Down syndrome,” he said. “By doing that, it’s our hope that we will actually be capable of then correlating clinical severity with a molecular signature from these tissues, thereby informing our ability to come up with tailored, personalized treatments to improve quality of life.”