A pioneering study has revealed significant differences in how oxygen functions and the way red blood cells operate in individuals with Down syndrome.
A significant study featured in Cell Reports by researchers from the Linda Crnic Institute for Down Syndrome (Crnic Institute) at the University of Colorado Anschutz Medical Campus highlights crucial variations in oxygen physiology and red blood cell behavior in those with Down syndrome. This research forms a part of the ongoing Human Trisome Project, a comprehensive study focusing on the Down syndrome population, which includes extensive clinical data, the largest biobank for Down syndrome analysis to date, and multi-omics datasets.
The team at the Crnic Institute began their investigation by analyzing numerous blood samples to pinpoint the physiological differences between individuals with Down syndrome and those from the general populace. They found that the triplication of chromosome 21, responsible for Down syndrome, induces a physiological condition similar to hypoxia, or low oxygen levels. They detected significant alterations in gene expression that suggest low oxygen availability, such as the activation of many hypoxia-responsive genes and proteins, as well as heightened levels of factors essential for creating heme, the component that carries oxygen within red blood cells.
“These findings emphasize that hypoxia and the signaling related to it should be a central focus when discussing the health of individuals with Down syndrome,” explains Dr. JoaquÃn Espinosa, executive director of the Crnic Institute, pharmacology professor, principal investigator of the Human Trisome Project, and one of the paper’s senior authors. “Understanding what causes hypoxiaand its repercussions on health is vital, as this could lead to effective strategies to enhance oxygen supply in this vital population.”
“The results are astonishing; we can confidently say that the blood of individuals with Down syndrome resembles that of someone who has been rapidly taken to high altitudes or has been administered erythropoietin (EPO), the key regulator in creating new red blood cells,” states Dr. Micah Donovan, lead author of the study. “While it has long been acknowledged that individuals with Down syndrome tend to have fewer and larger red blood cells, this study is the first to show that they overproduce EPO and are undergoing stress erythropoiesis—a process where the liver and spleen begin manufacturing red blood cells to supplement those produced by the bone marrow.”
The researchers found similar phenomena in a mouse model of Down syndrome, further supporting the idea that these important physiological changes stem from genetic material triplication and overexpression of certain genes.
“The continuity of hypoxic signaling and stress erythropoiesis in the mouse model allows for detailed studies that could pinpoint the associated genes and uncover potential therapies to improve oxygen physiology in Down syndrome,” notes Dr. Kelly Sullivan, associate professor of pediatrics, director of the Experimental Models Program at the Crnic Institute, and co-author of the study.
The team also examined whether the elevated hypoxic signaling and resulting stress erythropoiesis were linked to the heightened inflammatory state often seen in Down syndrome. They found that while individuals with more pronounced hypoxic signatures displayed significant immune system dysregulation and increased inflammation markers, reducing inflammation alone was insufficient to amend the hypoxic condition.
“We require much more data to discern the root causes behind the hypoxic state and its effects on the health of individuals with Down syndrome,” states Dr. Matthew Galbraith, assistant research professor of pharmacology, director of the Data Sciences Program at the Crnic Institute, and one of the paper’s senior authors. “Potential causes of the hypoxic state may include obstructive sleep apnea (common in individuals with Down syndrome), cardiopulmonary issues, or even potential defects in red blood cell function. We are very enthusiastic about several ongoing clinical trials funded by the NIH INCLUDE Project targeting obstructive sleep apnea in Down syndrome, which we believe will provide valuable insights.”
The Crnic Institute research team is already planning additional studies, aiming to uncover methods to enhance oxygen physiology for those with Down syndrome.
“This is yet another tremendous advancement from our scientists at the Crnic Institute that we hope will expedite the development of new treatments,” says Michelle Sie Whitten, president & CEO of the Global Down Syndrome Foundation, which collaborates closely with the Crnic Institute. “As a mother of a brilliant 21-year-old with Down syndrome, I am eager to learn how to safely normalize oxygen physiology and understand how this could better the lives of millions of individuals with Down syndrome worldwide. We take pride in how GLOBAL’s advocacy efforts with Congress and the National Institutes of Health (NIH) have contributed to the creation of the trans-NIH Down syndrome funding project, INCLUDE, which supports this and numerous other transformative studies and clinical trials.”
