The Global Down Syndrome Foundation (GLOBAL) is proud to support a
groundbreaking new study published in Cell Reports by
researchers from its partner and Affiliate, the Linda Crnic
Institute for Down Syndrome (Crnic Institute) at the University of
Colorado Anschutz Medical Campus, that reports important
differences in oxygen physiology and red blood cell function in
individuals with Down syndrome. The study is part of the ongoing
Human Trisome Project, a large and detailed cohort study of the
population with Down syndrome, including deep annotation of
clinical data, the largest biobank for the study of Down syndrome
to date, and multi-omics datasets.
The Crnic Institute team first analyzed hundreds of blood
samples to identify physiological differences between research
participants with Down syndrome versus controls from the general
population. They observed that triplication of chromosome 21, or
trisomy 21, the chromosomal abnormality that causes Down syndrome,
leads to a physiological state reminiscent of hypoxia, or low
oxygen. They identified major changes in gene expression indicative
of low oxygen availability, including induction of many
hypoxia-inducible genes and proteins, as well as increased levels
of factors involved in the synthesis of heme, the molecule that
transports oxygen inside red blood cells.
“These results reveal that hypoxia and hypoxic signaling should
be front and center when we talk about the health of people with
Down syndrome,” says Dr. Joaquín Espinosa, executive director of
the Crnic Institute, professor of Pharmacology, Principal
Investigator of the Human Trisome Project, and one of the senior
authors of the paper. “Given the critical role of oxygen physiology
in health and disease, we need to understand the causes and
consequences of hypoxia in Down syndrome, which could lead to
effective interventions to improve oxygen availability in this
deserving population.”
“The results are remarkable, it is safe to say that the blood of
people with Down syndrome looks like that of someone who was
quickly transported to a high altitude or who was injected with
erythropoietin (EPO), the master regulator of erythropoiesis, the
process of new red blood cell formation,” explains Dr. Micah
Donovan, lead author of the paper. “Although it has been
known for many years that people with Down syndrome have fewer and
bigger red blood cells, this is the first demonstration that they
overproduce EPO and that they are undergoing stress erythropoiesis,
a phenomenon whereby the liver and the spleen need to start
producing red blood cells to supplement those arising from the bone
marrow."
The team discovered that these phenomena are also observed in a
mouse model of Down syndrome, thus reinforcing the idea that these
important physiological changes arise from triplication of genetic
material and overexpression of specific genes.
“The fact that hypoxic signaling and stress erythropoiesis are
conserved in the mouse model paves the way for mechanistic
investigations that could identify the genes involved and reveal
therapeutic interventions to improve oxygen physiology in Down
syndrome,” explains Dr. Kelly Sullivan, associate professor of
pediatrics, Director of the Experimental Models Program at the
Crnic Institute, and co-author in the study.
The study team also investigated whether the elevated hypoxic
signaling and associated stress erythropoiesis was tied to the
heightened inflammatory state characteristic of Down syndrome.
Although individuals with the stronger hypoxic signatures show more
pronounced dysregulation of the immune system and elevated markers
of inflammation, their results indicate that lowering inflammation
does not suffice to reverse the hypoxic state.
“We will need a lot more data to understand what is causing the
hypoxic state and its impacts on the health of people with Down
syndrome,” says Dr. Matthew Galbraith, assistant research professor
of pharmacology, Director of the Data Sciences Program at the Crnic
Institute, and one of the senior authors of the paper. “The hypoxic
state could be caused by obstructive sleep apnea (which is common
in Down syndrome), cardiopulmonary malfunction, or even perhaps
defects in red blood cell function. We are very excited about
several ongoing clinical trials funded by the NIH INCLUDE
Project for obstructive sleep apnea in Down syndrome, which we
believe will be very informative.”
The Crnic Institute study team is already planning several
follow up studies, with the explicit goal of illuminating
strategies to improve oxygen physiology in the population with Down
syndrome.
“This is another huge breakthrough from our scientists at the
Crnic Institute that we hope will lead to additional treatments
quickly,” says Michelle Sie Whitten, president & CEO of Global
Down Syndrome Foundation, a partner and an Affiliate organization
of the Crnic Institute. “As a mother of a brilliant 21-year-old
with Down syndrome I am eager to understand how to normalize oxygen
physiology safely and how that may improve the lives of millions of
people with Down syndrome across the world. We are proud that
GLOBAL’s advocacy work with Congress and with the National
Institutes of Health (NIH) has led to the establishment of the
trans-NIH Down syndrome funding project, INCLUDE, that underwrites
this and numerous other groundbreaking studies and clinical
trials.”
About the Linda Crnic Institute for Down
Syndrome
The Linda Crnic Institute for Down Syndrome is one of the only
academic research centers fully devoted to improving the lives of
people with Down syndrome through advanced biomedical research,
spanning from basic science to translational and clinical
investigations. Founded through the generous support and
partnership of the Global Down Syndrome Foundation, the Anna and
John J. Sie Foundation, and the University of Colorado, the Crnic
Institute supports a thriving Down syndrome research program
involving over 50 research teams across four campuses on the
Colorado Front Range. To learn more, visit www.crnicinstitute.org
or follow us on Facebook and Twitter @CrnicInstitute.
About the University of Colorado Anschutz Medical
Campus
The University of Colorado Anschutz Medical Campus is a
world-class medical destination at the forefront of transformative
science, medicine, education and patient care. The
campus encompasses the University of Colorado health
professional schools, more than 60 centers and institutes, and two
nationally ranked independent hospitals - UCHealth
University of Colorado Hospital and Children's Hospital
Colorado – which see more than 2 million adult and
pediatric patient visits yearly. Innovative, interconnected and
highly collaborative, the University of Colorado Anschutz Medical
Campus delivers life-changing treatments, patient care
and professional training and conducts world-renowned research
fueled by $705 million in research grants. For more
information, visit www.cuanschutz.edu.
About Global Down Syndrome Foundation
The Global Down Syndrome Foundation (GLOBAL) is the largest
non-profit in the U.S. working to save lives and dramatically
improve health outcomes for people with Down syndrome. GLOBAL has
donated more than $32 million to establish the first Down syndrome
research institute supporting over 400 scientists and over 2,500
patients with Down syndrome from 33 states and 10 countries.
Working closely with Congress and the National Institutes of
Health, GLOBAL is the lead advocacy organization in the U.S. for
Down syndrome research and care. GLOBAL has a membership of over
100 Down syndrome organizations worldwide, and is part of a network
of Affiliates – the Crnic Institute for Down Syndrome,
the Sie Center for Down Syndrome, and the University of
Colorado Alzheimer’s and Cognition Center – all on the Anschutz
Medical Campus.
GLOBAL’s widely circulated medical publications
include Global Medical Care Guidelines for Adults with Down
Syndrome, Prenatal & Newborn Down Syndrome Information,
and the award-winning magazine Down Syndrome World TM.
GLOBAL also organizes the Be Beautiful Be Yourself Fashion
Show, the largest Down syndrome fundraiser in the world.
Visit globaldownsyndrome.org and follow us on social
media Facebook, X and Instagram.
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- GLOBAL self-advocate Connor Long bikes the Rocky Mountains
Cole Wilkes
Global Down Syndrome Foundation
(720) 548-5667
cwilkes@globaldownsyndrome.org
Allison Munk
Global Down Syndrome Foundation
(720) 548-5632
amunk@globaldownsyndromefoundation.org