PROJECT SUMMARY/ABSTRACT. This is a proposal for an administrative supplement for an active clinical trial award testing the safety and efficacy of a JAK inhibitor to decrease the burden of autoimmune conditions in Down syndrome. This supplement would fund an approved extension arm for select participants as well as travel expenses to facilitate inclusion of remote and diverse participants. The Specific Aims of the parent award have not changed. Trisomy 21 (T21) causes a different disease spectrum in people with Down syndrome (DS), protecting these individuals from some conditions, 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. The mechanisms driving this different disease spectrum are poorly understood, which creates a challenge in the clinical management of DS. Our team demonstrated 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. 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. 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. The approved extension arm will enable a more thorough assessment of the potential therapeutic benefits of JAK inhibition, provide additional data points, and also document the stability of changes observed.