Table 2.

New and experimental treatments.

Type of therapy	Mechanism of action	Compound/drug	Evidence	References
Drug Therapy	Increase cellular concentration of mitochondrial NAD+	KL1333	KL1333 has been shown to improve mitochondrial biogenesis and function in fibroblast line derived from a MELAS patient. No in vivo studies yet.	[82]
	Increase cellular concentration of mitochondria concentration	Omaveloxolone	Well tolerated and improved lowering heart rate and lactate levels during submaximal exercise, did not significantly change peak exercise workload in MM.	[83]
		REN001	PPAR β/δ agonist shown to improve fatigue and function in patients with fatty acid oxidation defects. Phase II trials in MM ongoing.	[84]
		Bezafibrate	Modest improvement in cardiac function and reduction in immunodeficient muscle fibers in MM patients	[85]
		Acipimox	Acipimox has been shown to improve mitochondria expression in vitro. Phase I clinical trials in adult MM patients ongoing.	[86,87]
	Protecting mitochondria from damage	Elamipretide	Shown to be associated with clinical and functional improvements in children and adults with MM.	[[88], [89], [90], [91], [92], [93]]
	Restoring mitochondrial homeostasis	Deoxynucleoside therapy	Use in patients with TK2 deficiency showed improved motor and respiratory function	[[94], [95], [96]]
	Enzyme replacement	Erythrocyte Encapsulated Thymidine Phosphorylase (EE-TP)	Use of patients with MNGIE showed clinical improvement and reductions in thymidine, and deoxyuridine.	[[97], [98], [99]]
Dietary supplementation	Correct taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR)	High dose taurine	Use in MELAS patients was shown to reduce frequency of stroke-like episodes and improved taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes	[100]
	Improve systemic NAD+ deficiency	Niacin	Oral niacin supplement increased blood NAD+ up to 8-fold and muscle NAD+ up to level of controls	[101,102]
	Influencing glutamate-glutamine cycle and glutamine transporters in the blood-brain barrier	High dose glutamine	Significant reduction in CSF glutamate and increment of CSF glutamine level in MELAS patients	[103]
	Stimulate mitochondrial function	Resveratrol	In vitro studies suggest improvements in mitochondrial fatty oxidation. However in vivo studies demonstrate lack of improvement in exercise capacity in adults with MM.	[104,105]
Dietary manipulation	Stimulate mitochondrial function	Ketogenic diet	Positive impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics	[106]
Exercise therapy	Improve oxidative capacity and activity tolerance	Aerobic training	Aerobic training improves mitochondrial volume. Uncertain effect on muscle strength, effort tolerance and quality of life.	[61,61,107,108]
Device	Reduce oxidative stress	Near-infrared light-emitting diode	In vitro evidence as an effective antioxidant therapy	[109,110]
	Modulate cortical and subcortical functional abnormalities	Transcranial direct current stimulation	Improved mitochondrial function and attenuated mitochondrial damage in mouse models. Aided improved clinical outcomes in autism, dyslexia and attention deficit.	[111,112]
Surgery	Alleviate symptoms due to ptosis-related impairment of visual axis and head posture	Ptosis surgery in CPEO	Ptosis surgery (levator resection or frontalis silicone sling surgery) in patients with CPEO showed statistically significant improvement in marginal-to-reflex distance (MDRI) and chin-up posture.	[113]
Gene therapy	tRNA modification		MTO1 overexpression fully restored 5-taurinomethyluridine frequency and partially increased the aminoacylation efficiency of MELAS tRNA, leading to the upregulation of mitochondrial protein synthesis and respiratory activity in MELAS myoblasts in vitro.	[114]
	AAV gene delivery		Administration of human NDUFS4 coding sequence by AAV2/9 and/or AAV-PHP.B vectors improved clinical phenotype and prolonged the lifespan in Leigh syndrome mouse models	[[115], [116], [117]]
			AAV9 delivery of human TK2 cDNA delaying disease onset and extending lifespan in mouse models.	[96]
	Mitochondrial targeting with recombinant oligoribonucleotides		In vitro studies showed improved heteroplasmy proportions of mutant mtDNA in cultured cells with KSS mtDNA deletion and with mtDNA ND5 point mutation.	[118,119]
	CRISPR-Cas9-mediated mitochondrial genome editing		In vitro studies in human cell lines and zebrafish has shown ability for this to target and reduce mtDNA copy number.	[120,121]
	CRISPR-free base editing		In vitro studies have shown application for mitochondrial base editing in human cell lines, mice, zebrafish and plants.	[[122], [123], [124]]