Mechanistic investigation of therapies for Down Syndrome Regression Disorder

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PROJECT SUMMARY. Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is a leading cause of intellectual and developmental disability, with an estimated prevalence of 1 in 700 live births. Individuals with DS display increased risk of numerous co-occurring neurological conditions including autism, seizure disorders, and Alzheimer’s disease (AD). Recently, an increasing number of reports have documented individuals with DS displaying a condition known as Down Syndrome Regression Disorder (DSRD), which include symptoms such as catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression. The etiology of DSRD is unclear, with affected individuals being subjected to highly heterogenous diagnostic work ups and disparate therapeutic interventions, including psychiatric medications (e.g., Lorazepam), electroconvulsive therapy (ECT), and intravenous immunoglobulin (IVIG). Therefore, additional research into the etiology of DSRD and the relative efficacy of different therapies is clearly needed. We propose here a comprehensive clinical research program that will not only advance our understanding of DSRD etiology, but which would also provide important information about the relative safety and efficacy of three different therapeutic approaches. Importantly, we hypothesize that many DSRD cases are driven by immune dysregulation affecting the central nervous system (CNS) and that these cases will benefit from immune- based therapies. Therefore, we propose to complete a comparative mechanistic investigation of three potential DSRD therapies: the benzodiazepine Lorazepam, IVIG, and the JAK inhibitor Tofacitinib. Our Specific Aims are: 1. To define the relative safety profile of Lorazepam, IVIG, and Tofacitinib in DSRD. We will complete a randomized, open-label, Phase II clinical trial for Lorazepam, IVIG, and Tofacitinib in individuals with DSRD with the primary endpoint being safety. 2. To compare the efficacy of Lorazepam, IVIG, and Tofacitinib in DSRD. Using key metrics for the evaluation of individuals with DSRD, a suite of secondary and tertiary endpoints will assess improvements in overall neurological health, activities of daily living, and quality of life, as well as domain-specific improvements in catatonia, movement and motor function, speech, sleep, and cognition. 3. To investigate potential mechanisms underlying DSRD and its response to therapies. Using biospecimens from individuals affected by DSRD collected during the trial and control samples from a companion active cohort study of individuals with DS, we will define biosignatures associated with DSRD diagnosis and the impact of each treatment modality on these biosignatures. Results from this phase II trial will generate much needed insights into DSRD etiology and treatment, paving the road for future larger trials to fulfill an unmet need in the DS community.