Therapies for Down Syndrome Regression Disorder

Who can take part

• 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

Who cannot take part

• Moyamoya syndrome or stroke (active or prior)
• IgA deficiency with antibodies against IgA
• Use of electroconvulsive therapy, lorazepam, or a JAK inhibitor within the last 4 weeks
• Use of immunosuppressant drugs (e.g., prednisone, mycophenolate mofetil, azathioprine) within the last 8 weeks
• 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
• 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
• 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; Co-occurring Conditions
• 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
• History of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster
• History of malignancy (solid tumor or leukemia)
• History of acute narrow-angle glaucoma
• History of venous or arterial thrombosis
• 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; Medications or Interventions
• Baseline abnormal renal function indicative of moderate or severe renal disease by eGFR <=45
• General
• 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
• Untreated hypothyroidism or hyperthyroidism
• Any vaccination planned during the study or within the last 6 weeks
• Use of IVIG 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 certain mood stabilizers or anticonvulsants (e.g., clonazepam, lithium, oxcarbazepine) within the last 4 weeks