# Pre-clinical assessment of JAK inhibitors to ameliorate cytokine storms in Down syndrome

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $257,044

## Abstract

ABSTRACT.
This application is being submitted to PA-18-591 in accordance with NOT-AI-20-031.
The recent emergence of SARS-CoV-2 and COVID-19 has created an urgent need for rapid deployment of
therapeutic strategies to combat the current pandemic, and major efforts are underway to develop new vaccines
and antiviral medications, however, results from these efforts are not expected in the near term. A more
immediate approach is to repurpose existing therapeutics approved by the FDA for other conditions to remediate
symptoms associated with the most severe COVID-19 outcomes, potentially saving lives and reducing the
burden on the healthcare system. Within this framework, cytokine release syndrome (CRS) also known as
cytokine storm or hypercytokinemia, has been implicated in acute respiratory distress syndrome, heart failure,
and death in patients with COVID-19 (1-5). However, although diverse immune-suppressive strategies to
attenuate the cytokine storm are being tested in clinical trials for COVID-19, there is a dearth of pre-clinical data
supporting their use to attenuate cytokine-driven pathology. Therefore, we propose here to test the ability of
FDA-approved inhibitors of Janus Kinases (JAKs) to mitigate rampant cytokine production and multi-organ
inflammation in a mouse model of non-infectious lethal immune hypersensitivity.
This mouse model has arisen directly from our work over the past five years that revealed a major role for immune
dysregulation in Down syndrome (DS). We demonstrated that individuals with Trisomy 21 (T21), the molecular
cause of DS, exhibit constitutively active interferon (IFN) signaling driven by presence of four of the six IFN
receptors (IFNRs), located in a single locus on chromosome 21 (chr21) (6). Follow-up studies have revealed 1)
signs of IFN activation and chronic inflammation, including numerous cytokines related to CRS, in the plasma
proteome of people with T21 (7, 8) and 2) widespread immune dysregulation and IFN hypersensitivity in the
blood of people with DS (9, 10). As part of our ongoing work to understand the role of interferon dysregulation in
Down syndrome (DS), we recently discovered that the Dp16 mouse model of DS is lethally hypersensitive to
chronic innate immune stimulation with the TLR3 agonist polyinosinic: polycytidylic acid [P(I:C)]. Unpublished
preliminary data in this proposal include:
 · P(I:C) treatment of Dp16 mice triggers release of cytokines, including several recently linked to poor
 prognosis in COVID-19, such as MCP-1, MIP-1α, and IP-10.
 · The lethal immune hypersensitivity in this model is associated with multi-organ inflammation and liver
 damage in particular.
 · The lethality, cytokine release, and inflammation induced by P(I:C) can all be blocked with the JAK1-
 specific inhibitor INCB054707.
We hypothesize that JAK inhibitors are a therapeutically viable strategy to ameliorate COVID-19
associated cytokine release syndrome and associated morbidities. As such, our proposal is resp...

## Key facts

- **NIH application ID:** 10163708
- **Project number:** 3R01AI145988-02S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kelly D. Sullivan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $257,044
- **Award type:** 3
- **Project period:** 2020-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163708

## Citation

> US National Institutes of Health, RePORTER application 10163708, Pre-clinical assessment of JAK inhibitors to ameliorate cytokine storms in Down syndrome (3R01AI145988-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10163708. Licensed CC0.

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