Modulation of the Immune System in Down Syndrome for Improved Outcomes and Neurodevelopment-1 (MISSION-1)

We are conducting a novel clinical trial of an immune-modulatory medicine in people with Down syndrome, funded by the Anschutz Acceleration Initiative and the Anna and John J. Sie Foundation.

On average, people with Down syndrome have widespread immune system dysregulation, which can impact many aspects of health. We have launched many studies to better understand this immune dysregulation and learn how to normalize it.

In this study, we will evaluate the safety and efficacy of a six-month treatment with the JAK1/3 inhibitor tofacitinib (or XELJANZ®) compared to placebo in individuals with DS ages 6-22 years old. The study will be conducted in a double-blind manner, meaning neither the study team nor the participant will know whether they are taking the study medicine or placebo.

Participants enrolled to the placebo arm may be given the option to participate in an open-label extension with tofacitinib after completion of the blinded portion of the study. Participants will be evaluated for improvements in their overall neurological health, daily activities, and quality of life. We will also collect blood to study changes in various proteins, metabolites, and antibodies.

On average, people with Down syndrome have widespread immune system dysregulation, which can impact many aspects of health. We have launched many studies to better understand this immune dysregulation and learn how to normalize it.

We will assess the following outcomes in individuals with Down syndrome:

Objectives:

To define the safety profile of tofacitinib treatment in DS.
To define the effects of tofacitinib on neurodevelopment in DS.
To define the effects of tofacitinib on overall health in DS.
To explore the effects of tofacitinib on the molecular pathophysiology of DS.

In addition, we will begin to ask if normalizing immune function with tofacitinib can improve other autoimmune conditions that people with Down syndrome are pre-disposed to and improve neurobehavioral function (cognition, behavior, motor function, language and social communication) or overall quality of life.

Mother holding young child with Down syndrome

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This study involves people with Down syndrome (ages 6 to 22 years, inclusive) weighing at least 10 kgs (~22 lbs.) with an available parent or guardian to complete study materials as appropriate.

The overall goal of this clinical trial is to understand if tofacitinib (XELJANZ®) is safe in people with Down syndrome. Participants will be closely monitored using blood tests, regular physical exams, and parent reports of any potential side effects. Based on findings in our previous clinical trials in adolescents and adults with DS, it is anticipated that tofacitinib will have a similar safety profile in people with Down syndrome as in the typical population.

Finally, our exploratory aims include beginning to measure the impacts, if any, of tofacitinib on other health conditions, transcriptomic, proteomic and metabolomic changes, and on cognition and quality of life.

Tofacitinib is an immunosuppressive medicine that inhibits key proteins in the interferon pathway called Janus kinases (or "JAKs"). We found the interferon pathway to be chronically activated in people with Down syndrome and believe it may be the key driver of immune dysregulation in people with Down syndrome. Therefore, inhibiting the JAK proteins may normalize immune function and positively impact multiple features of health in people with Down syndrome.

Tofacitinib has been studied in the general population and is approved by the FDA to treat psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Tofacitinib has also been studied in clinical trials to treat alopecia areata, dermatitis and eczema, psoriasis, and other autoimmune disorders that people with Down syndrome are more pre-disposed to.

Tofacitinib (or XELJANZ®) is a medicine that helps calm down an overactive immune system. It blocks certain proteins called JAKs, which are part of the body’s immune system. In people with Down syndrome, these proteins can sometimes work too much, causing inflammation and health problems. By blocking JAKs, tofacitinib may help reduce this overactivity.

The medicine has been used safely for other conditions, like arthritis, in both adults and children. Earlier studies showed that people with Down syndrome who used tofacitinib had good results with few side effects. This study carefully monitors each child for any side effects, making sure it’s safe for children with Down syndrome.

Participants: People ages 6 to 22 with Down syndrome.

Treatment: All enrolled participants will receive the medication or placebo for six months. Participants who receive the placebo may then qualify to receive the medication after completing initial visits.

Aims: To find out if the medicine is safe and helps improve health and quality of life.

Requirements: All enrolled participants will receive the medication or placebo, and will attend up to five study visits in Denver.

Participants who receive the placebo may qualify to receive the medication after completing the initial visits. These qualified participants will attend up to three more study visits in Denver.

Compensation: $100 per visit and up to $1,000 travel reimbursement per trip when applicable.

In 2016, we discovered that people with Down syndrome have chronically activated interferon signaling.

Interferon signaling is a branch of the immune system involved in fighting off viral infections. On average, people with Down syndrome have more interferon activity in their immune system than the typical population, even when they aren't fighting a virus. This is likely due to the fact that several important interferon genes are encoded on chromosome 21. We published this discovery in eLife in 2016.1 Interestingly, scientific literature in the field hinted at this as far back as the 1970's, but the exact mechanism and effects of increased interferon signaling in Down syndrome had yet to be well characterized. This was the beginning of what has become a robust immune research program at the Crnic Institute. 

Interferon signaling likely contributes to many hallmarks of Down syndrome, including common co-occurring conditions.

When interferon signaling is activated, the result is inflammation. And in fact, we showed that biomarkers in the blood of people with Down syndrome point to a state of chronic inflammation, published in Scientific Reports in 2017. 

It's not hard to imagine how systemic inflammation over a sustained time could have significant impacts on the immune system specifically, and the entire body more broadly. We thus embarked on in-depth characterizations of people with Down syndrome using samples from the Human Trisome Project, including:

Mapping 100 immune cell subsets using advanced technology, published in Cell Reports in 2019.

Characterizing T cell differentiation and function, published in PNAS in 2019.

Evaluating metabolic pathways in plasma and cerebral spinal fluid, published in Nature Communications in 2019.

In each study, we found specific changes in the immune systems and metabolism of people with Down syndrome that are associated with various autoimmune, neurological, and neurodegenerative conditions in the general population.

We hypothesize that normalizing interferon signaling in people with Down syndrome could have many benefits.

If chronically active interferon signaling contributes to negative health impacts in people with Down syndrome, one obvious next question is, "how can we stop it?" Thankfully, the interferon signaling pathway has been a popular target for medicine development in recent years, so there are a lot of tools already at our disposal. For example, we followed two people with Down syndrome who had alopecia areata (an autoimmune disorder causing hair loss) that didn't respond to traditional treatment. They both started taking a medicine called tofacitinib, which inhibits a family of proteins called JAKs in the interferon pathway, and both saw remarkable re-growth of their hair. We published these case reports in JAAD Case Reports in 2019 and continue to follow these and other individuals who are benefiting from tofacitinib. We also documented the benefits of JAK inhibition for the treatment of psoriatic arthritis in Down syndrome, published in 2021 in Rheumatology, and for the treatment of Down Syndrome Regression Disorder (DSRD), published in the Journal of Neuroimmunology in 2024.

Using mouse models of Down syndrome, we demonstrated that hyperactive interferon signaling contributes to many of the hallmarks of Down syndrome, including immune hypersensitivity, congenital heart defects, cognitive impairments, and craniofacial abnormalities. These findings were published in Nature Genetics in 2023. We also analyzed the effects of high interferon activity in hundreds of individuals with Down syndrome, showing that interferon hyperactivity correlates with the immune dysregulation characteristic of this condition and that JAK inhibition can normalize interferon signaling down to a normal range. These findings were published in Science Advances in 2023.

Encouraged by these large body of evidence, we launched the first clinical trial for JAK inhibition in Down syndrome for individuals 12-50 affected by autoimmune skin conditions. The first results from this trial showed that JAK inhibition attenuates the autoimmune burden in Down syndrome with a good safety profile, and these findings were published in eLIFE in 2024.11 This led to a second trial comparing JAK inhibition to other therapies for the treatment of Down Syndrome Regression Disorder (DSRD). This second trial focused on DSRD is currently recruiting.

Now, in this third clinical trial, we aim to more comprehensively test the safety of tofacitinib in younger children with Down syndrome and evaluate safety and potential benefits on health outcomes and brain function. This clinical trial will greatly advance our understanding of how interferon signaling and immune dysregulation contribute to many hallmarks of Down syndrome, eventually leading to better, more personalized medical care for people with Down syndrome.

Linda Crnic Institute for Down Syndrome

CU Anschutz

Research Complex II

12700 East 19th Avenue

Room 4014

Aurora, CO 80045

303-724-6599

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Linda Crnic Institute for Down Syndrome

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Modulation of the Immune System in Down Syndrome for Improved Outcomes and Neurodevelopment-1 (MISSION-1)

We are conducting a novel clinical trial of an immune-modulatory medicine in people with Down syndrome, funded by the Anschutz Acceleration Initiative and the Anna and John J. Sie Foundation.

Curious to learn more? Expand each of the boxes below to keep reading.

Linda Crnic Institute for Down Syndrome

Modulation of the Immune System in Down Syndrome for Improved Outcomes and Neurodevelopment-1 (MISSION-1)

We are conducting a novel clinical trial of an immune-modulatory medicine in people with Down syndrome, funded by the Anschutz Acceleration Initiative and the Anna and John J. Sie Foundation.

Curious to learn more? Expand each of the boxes below to keep reading.

Clinical Trial Design

What Are the Potential Treatments?

Is the Medicine Safe?

What Does the Study Involve?

The Science Behind It All

Linda Crnic Institute for Down Syndrome