Spironolactone Improved Children With Gene Mutations Related to NCOR
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age3-10
SponsorQilu Hospital of Shandong University
About this trial
MECP2, a key transcriptional regulator, has been shown to interact with the NCOR1/2 complex to modulate gene expression. Specifically, MECP2 recruits the NCOR complex to specific genomic loci, facilitating histone deacetylation and chromatin remodeling, which are essential for the proper regulation of genes involved in synaptic function and neuronal maturation. Disruptions in the MECP2-NCOR interaction have been implicated in neurodevelopmental disorders, including Rett syndrome and autism spectrum disorder (ASD), highlighting the collaborative role of MECP2 and the NCOR1/2 complex in maintaining neuronal homeostasis.
Building on this, NCOR1/2 constitutes the NCOR complex,interacts with many different nuclear receptors to produce special physiological effects. The receptors further recruit epigenome-modifying enzymes that are involved in the transcription of multiple genes involved in neurotransmission and synaptic plasticity. Studies of mice with gene knockout and autistic with NCOR mutations have found that both exhibit clinical symptoms characteristic of ASD, such as deficits in social interaction, spatial learning, and impaired recognition memory. Further study revealed that the cause was the hyperexcitability of GABAergic neurons in the lateral hypothalamus (LH) due to the NCOR1/2 defect, which impaired synaptic plasticity in the hippocampal CA3 region through the single synaptic LHGABA-CA3 neural projection, and thus exhibited learning/memory impairment. Therefore, drugs that affect the NCOR receptor can improve learning/memory impairment by affecting GABA neurons. Spironolactone is a widely used diuretic with good safety. Spironolactone is widely used in the treatment of hypertension, edema, and anti-androgen therapy in children. Spironolactone is currently under investigation as a potential treatment for children with NCOR gene mutations. Preclinical studies have demonstrated that spironolactone can ameliorate ASD-related symptoms in NCOR mutant mice, including reduced sensorimotor capacity, learning disability, and impaired working memory. Furthermore, the efficacy of related diuretics in the treatment of ASD has been demonstrated clinically. Therefore, spironolactone may represent a novel therapeutic target for patients with NCOR-related gene mutations in the future.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
ADOS-2 diagnostic criteria for autistic children
Patients with NCOR related gene mutation detected by whole exon test;
Age: 3-10 years old;
The subject and (or) guardian sign the informed consent, agreeing that the researcher will cooperate with the clinical trial process and collect clinical data and peripheral blood and urine samples;
Disqualifiers
have other pathogenic mutations (confidence higher than the NCOR related mutation);
Boys over 10 years old;
Allergic to spironolactone, used spironolactone one month before enrollment;
Hyperkalemia, serum potassium concentration > 5.5mmol/L;
Trial design
Design model
Single group
Treatments tested in this trial
.spironolactone
DrugIn the first week, the starting dose is 2mg/Kg per body weight once a day, taken with food at lunch every day, and subsequently adjusted according to the situation. If the patient's serum potassium is ≤5.0 mEq/L and the patient's serum creatinine is ≤2.5 mg/dL, treatment should be initiated with 25 mg spironolactone once daily. Increased to 100mg after remission. If the results are not obvious in the first month, increase the drug dose to 3mg/Kg.
Treatment groups
2 Participants
are divided into 1 treatment groupGroup A: spironolactone treatmentExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV)
Scores range from 40 to 130, with higher scores representing higher intelligence
Time frame
1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)2
Autism Diagnostic Observation Scale-2
The score ranges from 0 to 9, with higher scores indicating more severe autism
Time frame
1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)Secondary outcomes
1
Blood pressure
Including systolic and diastolic blood pressure
Time frame
1. Baseline 2. At the end of Cycle 1 (each cycle is 60 days) 3.At the end of Cycle 2 (each cycle is 60 days)2
The Score of Autism Behavior Checklist (ABC)
The Autism Behavior Checklist (ABC)63 was administered to screen for autism spectrum traits. Parents rated 57 items across five domains: Sensory, Relating, Body and Object Use, Language, and Social/Self-Help Skills. Total scores were classified to indicate the severity of autistic features.
Time frame
1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)3
The Score of Childhood Autism Rating Scale (CARS)
The Childhood Autism Rating Scale (CARS)62 provides a clinician-completed global evaluation of autism severity; total scores categorize individuals as non-autistic (\<30), mildly-to-moderately autistic (30-36.5), or severely autistic (≥37).
Time frame
1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)4
the score of Vineland Adaptive Behavior Scales, Third Edition (Vineland-3)
Adaptive functioning was evaluated using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) 64, which assesses Motor Skills (MOT), Communication (COM), Daily Living Skills (DLS), and Socialization (SOC). Parent-reported scores were stratified into Very Superior (130-140), Superior (115-129), Average (86-114), Low (71-85), or Very Low (≤70)
Time frame
1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)Sponsors and contacts
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Source ClinicalTrials.gov