false
zh-CN,zh-TW,en,fr,de,ja,ko,pt,es,th,vi
Catalog
2023 ACMG Annual Clinical Genetics Meeting Digital ...
Small molecule, high throughput drug discovery for ...
Small molecule, high throughput drug discovery for Kabuki Syndrome
Back to course
Pdf Summary
Kabuki syndrome (KS) is a rare genetic disorder that affects multiple systems in the body. Loss-of-function variants in KMT2D and KDM6A genes are associated with Kabuki syndrome. Previous studies have shown that some functional deficits of KS can be rescued postnatally. Therefore, researchers have been working to identify small molecule drugs that can increase expression of KMT2D or KDM6A and restore downstream effects on different pathways.<br /><br />To screen for potential drugs, the researchers engineered cell lines with partial promoter regions of KMT2D or KDM6A genes. These cell lines were then screened using a high content imaging system and tested against three libraries of 2,459 compounds at four different doses. The screening process involved measuring the average integrated intensity and cell number of the cells.<br /><br />From this screening process, a total of 31 small molecules were identified that significantly increased expression in one or both cell lines. These compounds were further validated using high-throughput screening and dose response curves. Eight out of the 31 compounds showed appropriate dose response curves and EC50 profiles in both cell lines.<br /><br />The next steps for the researchers include verifying the impact of the drug candidates on gene expression using qPCR, investigating the modulation of protein levels using Western Blot, confirming changes in histone modification by ELISA, and assessing if the drug candidates can restore the epigenetic signature in patient derived cell lines.<br /><br />The researchers are currently conducting additional pre-clinical validation in patient derived cell lines and different KS model organisms. They aim to prepare for clinical trials to determine the effectiveness of these small molecule drugs in treating Kabuki syndrome.
Asset Subtitle
Presenting Author - Xiaoting Ma, PhD; Co-Author - Christina Y. Hung, MD; Co-Author - Olaf A. Bodamer, MD, PhD, FACMG;
Meta Tag
Cognitive Disorders
Dysmorphology
Epigenetics
Intellectual disability
Methylation
Therapy
Co-Author
Christina Y. Hung, MD
Co-Author
Olaf A. Bodamer, MD, PhD, FACMG
Presenting Author
Xiaoting Ma, PhD
Keywords
Kabuki syndrome
genetic disorder
KMT2D gene
KDM6A gene
small molecule drugs
cell lines
screening process
gene expression
dose response curves
clinical trials
© 2025 American College of Medical Genetics and Genomics. All rights reserved.
×