Research

Down Syndrome Research

Down syndrome is not a disease; therefore, our lab is not focused on “curing” Down syndrome. Instead, we aim to improve quality of life by addressing common phenotypes and co-occurring conditions in people with Down syndrome, including developmental delays, autoimmune conditions, leukemia, cardiovascular abnormalities, Alzheimer’s disease and more.

Our research aims to understand the gene networks altered by the presence of an extra copy of chromosome 21 (called trisomy 21), decipher their impacts on biology, and identify safe therapeutic options. These efforts coalesce in the Crnic Institute Human Trisome Project®, a biobank paired with multi-omics analyses aimed at understanding why individuals with Down syndrome are more susceptible to certain conditions, such as Alzheimer’s disease, while they are protected from others, including many solid tissue-derived cancers. Our ultimate goal is to advance a personalized medicine approach to Down syndrome while also creating therapeutic leverage - enabling discoveries for millions of others who are affected by any one of the many medical conditions modulated by trisomy 21.

Human Trisome Project data is open to the public through the online research portal called the TrisomExplorer.

One of the most important studies we are performing in this context is a clinical trial entitled "Safety and efficacy of tofacitinib for immune skin conditions in Down syndrome." With this study, we are taking a discovery made by the Human Trisome Project – that trisomy 21 causes hypersensitive interferon signaling, leading to immune dysregulation – and testing a JAK inhibitor to mitigate the interferon response and resulting phenotypes – in this case, a collection of skin conditions driven by immune dysregulation that are more common in individuals with Down syndrome. We are also beginning to assess whether JAK inhibitors could improve other common conditions in Down syndrome, such as hypothyroidism and cognitive impairment.

Dr. Espinosa is Executive Director of the Linda Crnic Institute for Down Syndrome, co-leader of the INCLUDE DCC and the Espinosa Lab partners closely with Crnic Institute Members to advance research in Down syndrome.

Using complementary genomics analyses, this publication identifies the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.

This publication describes how the team employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-α) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS

At the molecular and cellular levels, people with Down syndrome show markers of chronic autoinflammation, including interferon hyperactivity, elevated levels of many inflammatory cytokines and chemokines, and changes in diverse immune cell types reminiscent of inflammatory conditions observed in the general population. However, the impact of this immune dysregulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and CoV disease of 2019 (COVID-19) remains unknown. This Perspective outlines why individuals with Down syndrome should be considered an at-risk population for severe COVID-19. Specifically, the immune dysregulation caused by trisomy 21 may result in an exacerbated cytokine release syndrome relative to that observed in the euploid population, thus justifying additional monitoring and specialized care for this vulnerable population.