Table 2.

Potential therapeutic approaches of BTHS. BTHS treatments focus on restoring TAZ protein and targeting mitochondrial dysfunction and CL biosynthesis. ROS: reactive oxygen species; RYR: ryanodine receptor; iPLA2: calcium-independent phospholipases A2.

	Therapy	Mechanism	Clinical Trial
Targeting Mitochondrial Dysfunction	Bezafibrate	Pan peroxisome proliferator-activated receptors (PPARs) agonist that promotes transcription activation of genes involved in oxidative metabolism and mitochondrial biogenesis [55,132,133,134].	CARDIOlipin MANipulation (CARDIOMAN) [132]
	Elamipretide	Water-soluble, aromatic-cationic, mitochondria-targeting tetrapeptide to improve mitochondrial function [71,135,136,137,138].	TAZPOWER [135,137]
	ROS scavenger or CaMKII inhibitor	Partially rescues Ca2+ handling defects in cardiomyocytes by attenuating ROS-triggered RYR phosphorylation [69,71].	N/A
Restoring TAZ in BTHS	Adeno-associated virus (AAV) Gene Therapy	AAV9 mediated TAZ gene delivery [14,139].	N/A
	Enzyme replacement therapy (ERT)	Recombinant human TAZ fused to a cell- penetrating peptide (hTAZ-CTP).	N/A
Targeting CL Biosynthesis	Linoleic acid (LA)	Increased incorporation of linoleoyl groups into nascent CL resulting in the production of mature CL without requiring the remodeling process [71,140,141].	N/A
	Bromoenol lactone (BEL)	Inhibition of iPLA2 by BEL blocks initiation of the CL remodeling process, ameliorating the increase in MLCL observed in BTHS [71,74,142,143,144].	N/A