Table 1.

Summary of LAMA2 MD therapeutic strategies discussed in the review

Purpose	Strategy	Method/drug	Comments; challenges	Main ref/s
Basement membrane treatment	Laminin-α2 replacement and substitution	Laminin-α2 replacement	Cell therapy a potential approach, transgenic mice show disease amelioration; laminin-α2 immunogenicity could be an issue	64,69
		Laminin-α1 provision	Functionally compensates for laminin-α2; large cDNA size poses delivery issues, laminin-α1 is not exactly laminin-α2	74,76
	Laminin-111 therapy	Reduces dystrophy in LAMA2 MD mice, laminin-111 can be derived from EHS tumors; pharmacokinetic study recommended	82,83
	Use of linker proteins	Mini-agrin	Enhances laminin association to α-dystroglycan; very focused, may need to be used with other linker proteins or therapies	86
	αLNND	Enhances laminin polymerization and binding to collagen IV; same challenge as for mini-agrin	93,95
	Adjusting integrin expression	α7 integrin overexpression	Transgenic LAMA2 MD mice had moderately improved lifespan, muscle function; other integrin targets can be explored	96
β1 integrin inhibition	RGD inhibition of β1 integrin activity improved ECM composition, myofiber stability; more research into the role of α7β1 in disease	97
Modulating cellular events caused by laminin-α2 loss	Enhancing cell growth	IGF-1, clenbuterol	Improved myofiber size, generally partial improvements on health and survival; treatment dose, administration, regimen needs work	100,103
	Reducing apoptosis	Bax inhibition, Bcl2 expression	Disease amelioration was successfully observed in transgenic mice; need to find a way to alter expression pharmacologically	104
	Omigapil, doxycycline	Recently completed phase I clinical trial for omigapil in LAMA2 MD therapy; efficacy and other outcomes to be released	106,108,109
	Inhibiting the immune response and fibrosis	Losartan, TXA127	TXA127 granted Orphan Drug status for treating LAMA2 MD; exact information on safety and efficacy remains to be seen	113,118
	Prednisolone, halofuginone, GTA, FTS, C3, galectin-3, osteopontin	Various effects on LAMA2 MD disease, from helpful to harmful; each needs in-depth study, side effects have to be considered	122–126
	Targeting other intracellular systems of regulation	Proteasome inhibition (MG-132, bortezomib)	Partially useful to having no effect at all in ameliorating LAMA2 MD; rethinking of the approach or search for more targeted inhibitors recommended	127–129
		Autophagy inhibition (3-MA)	Partially useful in ameliorating LAMA2 MD; same challenge as for proteasome inhibition	130
		Reducing calcium levels and its effects (caldecrin, cyclophilin D inactivation)	Promising results for LAMA2 MD treatment; however, studies are very preliminary and more research into other outcomes of treatment is required	131,132
		Targeting metabolism (metformin)	Gender-specific therapeutic effect observed; mechanism of action largely unknown	133
Targeting glycosylation (CT GalNAc transferase overexpression)	Ameliorates LAMA2 MD in dystrophic mice; mechanism of action also unclear, but may be linked to enhancing agrin expression	134
Genetic correction	Exon skipping	Lama2 exon 4 skipping PMO	Laminin-α2 protein production was restored in the dy3K model, and dystrophic symptoms were treated; PMO delivery can be improved, patient applicability currently limited	138
	CRISPR/Cas9	Exon 2 inclusion	Lama2 mutation corrected in the dy2J model, laminin-α2 production rescued, treated animals significantly improved; off-target effects are a concern, need strategies for other mutations	140
Lama1 overexpression	Lama1 expression was induced in vitro and in vivo, can potentially be used for other attractive targets, eg agrin; assessment of functional effects lacking	141

Abbreviations: IGF-1, insulin-like growth factor 1; GTA, glatiramer acetate; FTS, farnesylthiosalicylic acid; C3, complement 3; 3-MA, 3-methyladenine; CT, cytotoxic T cell; PMO, phosphorodiamidate morpholino oligomer; EHS, Engelbreth-Holm-Swarm; ECM, extracellular matrix.