Table 3.

Current studies investigating effects of THs, TH analogs and other therapies on the myelination phenotype in models of MCT8 deficiency and human AHDS patients.

Model	Phenotype	Drug	Dose	Window	Effect	References
mct8−/− zebrafish	Reduced p0, olig2, mbp, plp1b expression Reduced OL numbers Reduced OL extensions Hypomyelination	T3	0.5 nM	0–3 dpf	None	(129)
		T4
		Triac			p0 expression rescued
		Tetrac
		Ditpa	5 nM
		T3			Rescue OL numbers	(132)
		Triac
		Ditpa
		clemastine (Tavist)	500 nM
		T3	5 nM	6–10 dpf	None
		Triac			Rescue OL numbers
		Ditpa			Partial rescue OL numbers
		clemastine (Tavist)	500 nM
		pT2-fli:Mct8-tagRFP construct to express Mct8 in ECs of the BBB	50 ng/μl	0–10 dpf	No effect at 3 dpf Number of OLs rescued at 10 dpf
Mct8/Oatp1c1−/− mouse	Severe persistent hypomyelination Many axons unmyelinated Decreased MBP immunoreactivity Reduced WM thickness	Triac	50 ng/g BW/day 400 ng/g BW/day	P1–P12	None Normalization of myelination	(139)
Normal NKX2.1-GFP human embryonic stem cells	None	T3	40 ng/mL	21 days	Promotion of cell cycle exit OL differentiation TFs myelin gene expression	(90)
		Ditpa T3 + Ditpa	10 ng/mL 10 ng/mL + 40 ng/mL, resp.		Strong promotion of cell cycle exit OL differentiation TFs myelin gene expression
Normal NKX2.1-GFP human embryonic stem cells in coculture with retinal ganglion cells		T3	40 ng/mL	7 days	Far less potent than Ditpa alone
		Ditpa	10 ng/mL		Increased number of myelinated axons more OL contacting axons amount of myelin/axon unchanged
		T3 + Ditpa	10 ng/mL + 40 ng/mL, resp.		Less potent than Ditpa alone
MCT8-deprived NKX2.1-GFP human embryonic stem cells in coculture with retinal ganglion cells	OL apoptosis Impaired myelination	T3	40 ng/mL	day 3-5 after MCT8-KD	None
		Ditpa	10 ng/mL		Promotion of OPC survival
		T3 + Ditpa	10 ng/mL + 40 ng/mL, resp.
		T3	40 ng/mL	7 days after MCT8-KD	None
		Ditpa	10 ng/mL		Increased myelin segments
		T3 + Ditpa	10 ng/mL + 40 ng/mL, resp.
4 AHDS patients	Delayed myelination at 9 months of age (two twins)	Ditpa	Steady build-up to 3X/day 0.97–1.21 mg/kg BW (Month 4–10) Steady build-up to 3X/day 2.0–2.4 mg/kg BW (Month 15–29)	Started at month 25	Normal myelination 47 months of age	(144)
	Delayed myelination 3, 8, 13 months of age			Started at month 8.5	None*
	Delayed myelination at 5 months of age			Started at month 25	None*

BBB, blood-brain barrier; BW, body weight; dpf, days post-fertilization; EC, endothelial cell; KD, knockdown; MBP, myelin basic protein; OL, oligodendrocytes; Olig2, oligodendrocyte transcription factor; OPC, oligodendrocyte precursor cell; P, postnatal day; p0, Myelin protein zero; plp1b, proteolipid protein 1b; TF, transcription factor; WM, white matter.