TY  - EJOU
AU  - He, Jun 
AU  - Luo, Jianli 
AU  - Wang, Yanling 
AU  - Zhou, Dai 
AU  - Xiang, Shuanglin 

TI  - Precision Pharmacology in Pediatric Congenital Heart Disease: Gene Editing and Organoid Models Addressing Developmental Challenges
T2  - Structural and Congenital Heart Disease

PY  - 2025
VL  - 20
IS  - 5
SN  - 3071-1738

AB  - Pediatric congenital heart disease (CHD) pharmacotherapy faces three fundamental barriers: developmental pharmacokinetic complexity, anatomic-genetic heterogeneity, and evidence chain gaps. Traditional agents exhibit critical limitations: digoxin’s narrow therapeutic index (0.5–0.9 ng/mL) is exacerbated by <i>ABCB1</i> mutations (toxicity risk increases 4.1-fold), furosemide efficacy declines by 35% in neonates due to NKCC2 immaturity, and β-blocker responses vary by <i>CYP2D6</i> polymorphisms (poor metabolizers require 50–75% dose reduction). Novel strategies demonstrate transformative potential—CRISPR editing achieves 81% reversal of <i>BMPR2</i>-associated pulmonary vascular remodeling, metabolically matured cardiac organoids replicate adult myocardial energy metabolism for drug screening, and SGLT2 inhibitors activate triple mechanisms (calcium overload mitigation, mitophagy, fibrosis reversal). However, clinical translation requires overcoming developmental barriers: age-dependent enzyme expression (infant <i>CYP2D6</i> = 30–60% adult activity), post-Fontan hepatotoxicity (bosentan trough concentrations elevates 1.8-fold), and AI model limitations (32% error in complex CHD). Future integration of placental transfer models, disease-specific organoids, and multi-omics mapping of FOXO/CRIM1 pathways will shift paradigms from symptom control to curative repair.
KW  - Congenital heart disease; molecular pathogenesis; precision medicine; gene editing; translational challenges

DO  - 10.32604/chd.2025.071773