Therapies for Down Syndrome Regression Disorder

Eligibility Criteria

• * Individuals with DS between the ages of 8 and 30 years, inclusive. DS is broadly defined to include complete trisomy 21, Robertsonian translocation trisomy 21, partial trisomy 21 (segmental duplication), and mosaic trisomy 21.
• * Diagnosis of possible or probable DSRD per 2022 consensus guidelines.
• * Must agree to random treatment assignment.
• * Must agree to complete a washout of any medications intended to treat symptoms of DSRD or that may interfere with study interventions.
• * Must be able to present with a study partner or legal guardian at all study visits.
• * Weight less than 40 kg.
• * Pregnant or breast feeding.
• * Past or current tobacco smoking.
• * Poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements.
• * Known allergies, hypersensitivity, or intolerance to lorazepam, IVIG, or tofacitinib.
• * Participants may be excluded for other unforeseen reasons or confounding reasons for DSRD symptoms at the study doctor's discretion.
• * Any co-occurring genetic disorder.
• * Active symptomatic cardiac disease.
• * Clinically significant chronic or active viral infection, including but not limited to HIV, hepatitis, CMV, EBV, HSV or untreated tuberculosis.
• * Untreated chronic or active bacterial infection.
• * Untreated hypothyroidism or hyperthyroidism.
• * History of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
• * History of malignancy (solid tumor or leukemia).
• * Moyamoya syndrome or stroke (active or prior).
• * Baseline abnormal renal function indicative of moderate or severe renal disease by eGFR \<=45.
• * History of acute narrow-angle glaucoma.
• * History of venous or arterial thrombosis.
• * IgA deficiency with antibodies against IgA.
• * Pathogenic neuronal autoantibody positivity against established causes of autoimmune encephalopathy in CSF.
• * Any subject with a history of anaphylaxis or a severe systemic response to blood or plasma-derived products.
• * Any vaccination planned during the study or within the last 6 weeks.
• * Use of electroconvulsive therapy, lorazepam, or a JAK inhibitor within the last 4 weeks.
• * Use of IVIG within the last 8 weeks.
• * Use of immunosuppressant drugs (e.g., prednisone, mycophenolate mofetil, azathioprine) within the last 8 weeks.
• * Use of rituximab within the past 6 months, unless B cell levels have recovered and are above 50 cells/uL.
• * Use of other immunosuppressant biologics (e.g., adalimumab, etanercept) within the past 6 months.
• * Use of strong CP3A4 inhibitors or inducers (e.g., ketoconazole, rifampin) within the last 4 weeks.
• * Use of moderate CP3A4 inhibitors with a strong CYP2C19 inhibitor (e.g., fluconazole) within the last 4 weeks.
• * Use of moderate CYP2C9 inhibitors (e.g., valproic acid) within the last 4 weeks.
• * Use of strong CYP1A2 inducers (e.g., phenobarbital) or moderate CYP1A2 inhibitors (e.g., fluvoxamine) within the last 4 weeks.
• * Use of certain mood stabilizers or anticonvulsants (e.g., clonazepam, lithium, oxcarbazepine) within the last 4 weeks.
• * Any prior use of methotrexate, cyclophosphamide, or other chemotherapeutics.
• * Any prior solid organ transplant.
• * Any prior neurosurgical intervention.
• * Any subject who has received blood or plasma products ≤ 30 days prior to first Baseline visit.