R33AR077495

Jak Inhibition in Down Syndrome - Project Summary.

Trisomy 21 (T21) causes a different disease spectrum in people with Down Syndrome (DS), protecting these individuals from some diseases, while strongly predisposing them to others. For example, >50% of adults with T21 are affected by one or more autoimmune conditions, including a wide range of immune skin conditions.

Unfortunately, the mechanisms driving this different disease spectrum are poorly understood, which creates a challenge in the clinical management of DS. We recently discovered that T21 causes consistent activation of the interferon (IFN) response across diverse cell types, which is likely due to the fact that four of the six IFN receptors are encoded on Chr21.

Accordingly, T21 cells are hypersensitive to IFN stimulation, display hyperactivation of JAK/STAT signaling, and overexpress IFN-stimulated genes. Furthermore, dozens of inflammatory cytokines are dysregulated in people with DS, and T21 drives production of potent neurotoxic metabolites via the IFN-inducible kynurenine pathway.

Therefore, we hypothesize that hyperactivation of IFN signaling drives immune dysregulation and various pathologies in DS, and that pharmacological inhibition of IFN signaling could have multidimensional therapeutic benefits in this population.

Accordingly, we propose here to complete a first-in-kind clinical trial for a JAK inhibitor in DS. Our specific aims are:

1. To define the safety profile of JAK inhibition in people with Down Syndrome. We will perform an open-label Phase II clinical trial for tofacitinib, a JAK1/3 inhibitor, in people with DS and an active immune skin condition, with the main primary endpoint being the assessment of safety.

2. To determine the impact of JAK inhibition on the immune dysregulation caused by trisomy 21. Using blood samples collected during the trial, we will define the impact of JAK inhibition on a) IFN scores derived from the transcriptome of white blood cells, b) circulating levels of inflammatory cytokines elevated in people with DS, c) levels of neurotoxic metabolites in the IFN-inducible kynurenine pathway, and d) levels of key autoantibodies involved in autoimmune thyroid disease and celiac disease, two common co-occurring conditions in DS.

3. To define the impact of JAK inhibition on immune skin conditions in Down Syndrome. Using proven metrics currently employed in clinical trials of JAK inhibitors for immune skin conditions, our main secondary endpoint will be to determine whether JAK inhibition reduces skin pathology in DS.

4. To characterize the impact of JAK inhibition on cognition and quality of life in Down Syndrome. Using a battery of tests to evaluate cognition in DS, we will explore the impact of JAK inhibition on diverse cognitive functions. Decreased skin pathology may also affect overall perceived health and enjoyment, as well as have social implications, which will be measured by quality of life assessments.

The Regents Of The Univ. Of Colorado

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.310 - Trans-NIH Research Support

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Colorado United States

State-Wide

Clinical Trials Development for Co-Occurring Conditions in Individuals with Down syndrome: Phased Awards for INCLUDE (R61/R33 Clinical Trials Required) (RFA-OD-19-018)

Amendment Since initial award the total obligations have increased 300% from $1,103,667 to $4,419,892.