Spironolactone Improved Children With Gene Mutations Related to NCOR

NCT06678685 | Completed Phase 2

• 1 other identifier: QL000004
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

NCOR Gene Mutations; Spironolactone; ASD

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (7)

• 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)

  1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)

• The Score of Childhood Autism Rating Scale (CARS)

  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)

  1. Baseline ;2. At the end of Cycle 1 (each cycle is 45 days)

• the score of Chinese Communicative Development Inventory (CDI)

  1. Baseline 2. At the end of Cycle 1 (each cycle is 45 days)

Study Arms (1)

spironolactone treatment

EXPERIMENTAL

Drug: .spironolactone

Interventions

.spironolactone DRUG

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.

spironolactone treatment

Eligibility Criteria

• Age: 3 Years - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• ADOS-2 diagnostic criteria for autistic children
• Patients with NCOR1/2 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;

You may not qualify if:

• have other pathogenic mutations (confidence higher than the NCOR1/2 mutation);
• Boys over 10 years old;
• Allergic to spironolactone, used spironolactone one month before enrollment;
• Hyperkalemia, serum potassium concentration \> 5.5mmol/L;
• Renal insufficiency;
• Used related drugs one month before enrollment: potassium supplement, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, digoxin, coletenamine, acetylsalicylic acid, abiraterone;
• Fever (body temperature above 37.3°);
• 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.

Sponsors & Collaborators

• Qilu Hospital of Shandong University: lead

Study Sites (1)

Qilu Hospital of Shandong University

Jinan, Shandong, 250012, China

Location

MeSH Terms

Interventions

Spironolactone

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2024
• First Posted: November 7, 2024
• Study Start: October 30, 2024
• Primary Completion: October 30, 2025
• Study Completion: October 30, 2025
• Last Updated: March 19, 2026

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share

Locations

CN (1)