MAGT1 Deficiency
Conditions
Keywords
Decitabine
Brief summary
This is a single-arm, open-label, single-center, exploratory clinical trial evaluating the safety and efficacy of decitabine in male patients aged 1 month to 18 years with X-linked magnesium transporter 1 (MAGT1) deficiency. Eligible patients have a confirmed MAGT1 gene mutation leading to XMEN disease ( X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect). The study will assess changes in liver function, immune function, and NKG2D expression, as well as adverse events, over four treatment cycles and the follow-up period.
Detailed description
XMEN disease is a rare X-linked primary immunodeficiency caused by loss-of-function mutations in MAGT1, leading to chronic Epstein-Barr virus (EBV) infection, liver dysfunction, and reduced NKG2D expression on lymphocytes. TUSC3 shares functional redundancy with MAGT1 but is epigenetically silenced in immune and liver tissues. Decitabine, a DNA methyltransferase inhibitor, can reactivate TUSC3 expression. This single-arm, open-label, single-center study will enroll six male participants aged 1 month to 18 years with genetically confirmed MAGT1 mutation and a clinically diagnosis of XMEN disease. Eligible participants will receive decitabine intravenously at 20 mg/m² once daily for five consecutive days every four weeks, for a total of four cycles. Safety and efficacy will be evaluated by monitoring NKG2D expression, liver enzymes levels, EBV viral load, lymphocyte function, TUSC3 expression, and adverse events. Participants will be followed for 180 days after the last dose.
Interventions
DRUGDecitabine
Decitabine 20 mg/m² intravenous infusion once daily for 5 consecutive days every 4 weeks, for a total of 4 cycles.
Sponsors
Children's Hospital of Fudan University
National Natural Science Foundation of China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
1 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Male participants aged 1 month to 18 years old. 2. Confirmed MAGT1 gene mutation by genetic testing. 3. Clinical manifestations consistent with XMEN disease, including liver dysfunction and/or EBV infection. 4. Reduced lymphocyte NKG2D expression. 5. Vital signs within normal range at screening. 6. Expected survival ≥ 6 months. 7. Able to comply with study procedures. 8. Guardian and participant provide written informed consent.
Exclusion criteria
1. Hypersensitivity to decitabine or any excipient. 2. Hematopoietic stem cell transplantation within 1 year before enrollment. 3. Severe concurrent organ dysfunction or systemic disease. 4. Positive HBsAg, anti-HCV, syphilis, or HIV test. 5. Neurological or psychiatric disorders that impair compliance. 6. Participation in another clinical trial within 3 months. 7. Other conditions judged inappropriate by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement magnitude of serum liver enzyme levels | up to 6 months after the last dose | Analyze serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (γ-GT) levels at key time points (before the second dose, before the fourth dose, 3 months after the last dose, and 6 months after the last dose) calculate the reduction magnitude from baseline (\[(baseline value-target time point value) / baseline value\] × 100%) at each time point, and evaluate the trend of liver function recovery. |
| Changes in NKG2D expression levels | up to 6 months after the last dose | Changes in NKG2D expression levels of peripheral blood lymphocytes from baseline; the expression levels were analyzed before the second administration, before the fourth administration, and 3 months after the last administration, and the absolute change values from baseline were calculated for each time point. |
| Cumulative incidence of grade ≥3 myelosuppression | up to 6-month follow-up period after the last dose | Classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with observation periods covering the entire treatment duration (4 dosing cycles) and a 6-month follow-up period after the last dose. Criteria for determination: White blood cell count (WBC) \<1.0×10\^9/L or platelet count (PLT) \<25×10\^9/L in complete blood count (CBC). The proportion of patients meeting the above criteria was statistically analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in TUSC3 expression in peripheral blood lymphocytes | up to 6-month after the last dose | Quantitative analysis of relative mRNA expression levels (using real-time fluorescent quantitative PCR) and protein expression levels (using Western blot) was performed to describe the upregulation/downregulation trends and relative change magnitudes at each key node (corresponding to primary endpoints) compared to baseline. |
| Increase in cytotoxic activity of NK cells/T cells | up to 6 months after the last dose | Cytotoxic function assays were used to detect cytotoxic activity (expressed as kill rate%), and the absolute increase values (target time point kill rate-baseline kill rate) at each key node (same as primary endpoint) were calculated compared to baseline. |
| Cumulative incidence of coagulation dysfunction | up to 6 months after the last dose | Prolonged prothrombin time (PT)\> 3 seconds, prolonged activated partial thromboplastin time (APTT)\> 10 seconds, or international normalized ratio (INR)\> 1.5 in coagulation function tests. The proportion of patients meeting any one of these criteria was statistically analyzed at each key node (corresponding to primary endpoints). |
| Overall incidence rate of adverse events and severity grading | up to 6 months after the last dose | The occurrence time, duration, severity (graded according to CTCAE version 5.0), and association with the study drug (definitively related, possibly related, or unrelated) of AE were recorded. The overall incidence rate and the composition ratio of AE at each severity level were statistically analyzed. |
Countries
China
Contacts
CONTACTJia Hou, Ph.D., M.D.
CONTACTWenjie Wang, M.D.
PRINCIPAL_INVESTIGATORJia Hou, Ph.D., M.D.
Children's Hospital of Fudan University
Outcome results
None listed