TABLE 3.

Gene therapy strategies and application to hiPSC-CM models to restore dystrophin function.

Approach	Target mutation type	Dystrophin product	Strengths	Challenges	hiPSC-CM
Stop codon readthrough	Nonsense point mutations	Complete	• Well-tolerated (PTC124 or ataluren)	• Low efficiency in the heart • Low prevalence of amenable mutations • Frequent re-dosing	?
AON-mediated exon skipping	Frameshift mutations	Lacking existing deletion and additional exon(s)	• Well-tolerated • Effective at cell level	• Poor cardiac uptake of PMO • Frequent re-dosing • Low number of amenable mutations for each AON drug	• Efficacy • Reduced arrhythmias (Liang et al., 2019)
AAV micro-dystrophin	not interacting with endogenous gene)	Extensively truncated but functional	• High efficacy in heart • High efficacy in skeletal muscle • Lasting (multiple years)	• Potentially immunogenic • Potential for null effect with pre-existing immunity	?
CRISPR-Cas9	Frameshift, insertion, and nonsense mutations	Depends on editing strategy [ranging from complete to lacking deletion and additional exon(s)]	• High efficacy in heart and skeletal muscle • Versatile • Genomic correction is life-long (theoretically)	• Potentially immunogenic • Risk of off-target editing • Low number of amenable mutations for each CRISPR drug	• Efficacy • Restored contractile force of EHTs (Kyrychenko et al., 2017; Long et al., 2018; Min et al., 2019; Zhang et al., 2017)