Spironolactone Improved Children With Gene Mutations Related to NCOR

An Exploratory Study of Spironolactone Tablets for the Treatment of Children With Gene Mutations Related to NCOR

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.

Study Overview

• Status: Recruiting
• Conditions: ASD; Spironolactone; NCOR Gene Mutations
• Intervention / Treatment: Drug: .spironolactone

• Study Type: Interventional
• Enrollment (Estimated): 2
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Cao Aihua Qilu Hospital of Shandong University; Phone Number: 18560086317; Email: qlyyebk@163.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250012
      • Recruiting
      • Qilu Hospital of Shandong University
      • Contact: Aihua cao Cao; Phone Number: 18560086317; Email: qlyyebk@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ADOS-2 diagnostic criteria for autistic children
2. Patients with NCOR related gene mutation detected by whole exon test;
3. Age: 3-10 years old;
4. 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;

Exclusion Criteria:

1. have other pathogenic mutations (confidence higher than the NCOR related mutation);
2. Boys over 10 years old;
3. Allergic to spironolactone, used spironolactone one month before enrollment;
4. Hyperkalemia, serum potassium concentration > 5.5mmol/L;
5. Renal insufficiency;
6. Used related drugs one month before enrollment: potassium supplement, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, digoxin, coletenamine, acetylsalicylic acid, abiraterone;
7. Fever (body temperature above 37.3°);
8. Clinically significant metabolic, hematological, liver, immune, urological, endocrine, neurological, pulmonary, psychiatric, skin, allergic, renal, or other major conditions in the determination of ASD that may affect the interpretation of study findings or patient safety.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: spironolactone treatment

Drug: .spironolactone; In 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV)	Scores range from 40 to 130, with higher scores representing higher intelligence	1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)
Autism Diagnostic Observation Scale-2	The score ranges from 0 to 9, with higher scores indicating more severe autism	1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Including systolic and diastolic blood pressure	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)
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.	1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)
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).	1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)
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)	1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)
the score of Chinese Communicative Development Inventory (CDI)	Language development was analyzed using the Chinese Communicative Development Inventory (CDI)65, a parent-reported questionnaire that quantifies expressive/receptive vocabulary, syntactic complexity, and gestural communication across multiple subdomains (e.g., verbs, spatial terms, phrases).	1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)
the score of Conners Parent Symptom Questionnaire (CPRS)	Behavioral challenges were assessed using the Conners Parent Symptom Questionnaire (CPRS)66, which evaluates impulsivity-hyperactivity, conduct problems, learning difficulties, psychosomatic symptoms, and anxiety. Total scores were categorized as Normal, Borderline, or Abnormal.	1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)
The score of School-Age Children's Behavioral Rating Scale of Executive Function	The School-Age Children's Behavioral Rating Scale of Executive Function evaluated multiple cognitive control processes, including Initiation (ability to begin tasks independently), Working Memory (capacity to hold and manipulate information), Inhibition (control over impulsive responses), and Organization (skills in structuring tasks and materials). Higher scores on this scale indicate better executive function performance in daily activities.	1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)

Collaborators and Investigators

• Sponsor: Qilu Hospital of Shandong University

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: October 27, 2024
• First Submitted That Met QC Criteria: November 5, 2024
• First Posted (Actual): November 7, 2024

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Lactones; Pregnenes; Spironolactone
• Other Study ID Numbers: QL000004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No