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Kelly Sullivan, PhD
Researchers at the Linda Crnic Institute for Down Syndrome in the University of Colorado School of Medicine have secured three grants totaling $1 million to study the interplay between COVID-19 and Down syndrome
While little is known about COVID-19’s effects on people with Down syndrome, early studies suggest the SARS-CoV-2 virus results in more hospitalizations and deaths at a younger age in the population. With their new funding, researchers at the Crnic Institute aim to fill this knowledge gap and advance therapeutic strategies for both the Down syndrome and the general populations.
Joaquin Espinosa, PhD, professor of pharmacology and executive director of the Crnic Institute, received the first of the three grants in August from Fast Grants to investigate the impact of immune-modulatory strategies on COVID-19.
In early September, both Espinosa and Kelly Sullivan, PhD, assistant professor of pediatrics-developmental biology at the Crnic Institute, received funding from the National Institutes of Health (NIH) INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE).
“We are grateful to the NIH for identifying people with Down syndrome as a high risk population for COVID-19, and for acting quickly to fund research that could help save the lives of our children and adults from this terrible virus,” Michelle Sie Whitten, president and CEO of the Global Down Syndrome Foundation, said in a press release. The Foundation is an internationally renowned advocacy non-profit and an affiliate of the Crnic Institute.
Studies target hyperinflammation link
All three studies will look at a state of hyperinflammation that occurs all the time in people with Down syndrome and oftentimes in patients with severe COVID-19. Scientists at the Crnic Institute have been studying this form of immune hyperactivity for years and believe their discoveries can advance their understanding of COVID-19 in the Down syndrome population.
David Beckham, MD
“We have already shown that people with Down syndrome have substantial dysregulation in their immune systems, which could impact not only their initial response to SARS-CoV-2 and their clinical outcome if they become ill with COVID-19, but also the development of potential long-term sequalae,” Espinosa said. “Understanding each of these pieces is crucial for understanding the risks and developing proper medical care for people with Down syndrome who get COVID-19.”
Espinosa’s studies are designed to help illuminate the impacts of hyperactive interferon signaling and consequent immune dysregulation on the course of COVID-19 and the development of immunity against SARS-CoV-2 in people with Down syndrome.
To do this, he is teaming up with Tell Bennett, MD, associate professor of pediatrics-informatics and data science, to mine the National COVID Cohort Collaborative (N3C) database and generate a definitive characterization of COVID-19 in Down syndrome. Espinosa will also work with David Beckham, MD, associate professor of medicine-infectious disease, to investigate the immune responses in individuals with Down syndrome that survived a SARS-CoV-2 infection.
Espinosa also will use his own ongoing cohort study of people with Down syndrome – the Crnic Institute Human Trisome Project – to gather clinical data and blood samples and complete pan-omics analyses in this population.
Looking at JAK inhibitors for COVID-19
Led by Sullivan, Crnic Institute researchers will also test the ability of a class of drugs known as JAK inhibitors to normalize hyperactive interferon signaling in a mouse model of Down syndrome. JAK inhibitors are currently being evaluated in numerous clinical trials worldwide for their ability to treat COVID-19. Drug maker Eli Lilly recently announced that the JAK inhibitor baricitinib (Olumiant) in combination with the antiviral drug remdesivir shortened the duration of COVID-19 hospitalizations in the ongoing ACTT-II trial sponsored by the National Institute of Allergy and Infectious Disease (NIAID).
Tell Bennett, MD
Using a mouse model of Down syndrome, Sullivan’s team has shown that these mice are hypersensitive to immune activation with ‘viral-mimetic’ molecules, and that their increased pathology can be reversed with JAK inhibitors. With this new funding, Sullivan will test the ability of each of the four currently approved JAK inhibitors (Olumiant, Xeljanz, Rinvoq and Jakafi) in this mouse model of lethal immune hypersensitivity. He is also teaming up with David Orlicky, PhD, associate professor of pathology, to characterize the impact of hyperinflammation and JAK inhibition on key organs.
“This mouse model is profound because we can induce an exaggerated innate immune response that is similar to what we are seeing in COVID-19,” Sullivan said. “We can then quickly test the ability of drugs to normalize this response, so it isn’t as damaging. All the while, we’re not only gleaning insights into COVID-19, but also furthering our understanding of the immune system in Down syndrome. It’s incredibly valuable work.”
If found effective in their mouse model and in ongoing clinical trials, JAK inhibitors could play an important role in the treatment of COVID-19 in both individuals with Down syndrome and the general population by normalizing the hyperinflammation caused by SARS-CoV-2.
JAK inhibitors also may be beneficial to patients with Down syndrome who suffer from other conditions driven by hyperactive inflammation, such as autoimmune skin conditions that are more prevalent in this population. In collaboration with the Department of Dermatology, Espinosa’s team is currently performing a clinical trial for the JAK inhibitor Xeljanz in individuals with Down syndrome affected by autoimmune skin conditions, such as alopecia areata, psoriasis, vitiligo, hidradenitis suppurativa and atopic dermatitis.
“We’re not only gleaning insights into COVID-19, but also furthering our understanding of the immune system in Down syndrome. It’s incredibly valuable work.” – Kelly Sullivan, PhD
“I find it remarkable that the same class of drugs, JAK inhibitors, that we are testing here in Colorado to benefit people with Down syndrome affected by immune skin conditions are also being tested worldwide to treat COVID-19, with very promising initial results being announced as part of NIAID’s ACTT-II trial,” Espinosa said. “Who would have known that studying immune dysregulation in Down syndrome could also inform the management of the biggest viral pandemic of our time?”
Photo at top: Joaquin Espinosa, PhD, in his lab at the Crnic Institute.
Guest Contributor: Amanda Hill, Linda Crnic Institute for Down Syndrome