Table 2.

Examples of Splicing-based Therapeutic Approaches.

Disease	Gene	Aberrant Splicing	Therapy	References
SMA	Mutated: SMN1 Therapy: SMN2	Skipping of exon 7 due to C > T mutation at position 6 of exon 7	2′OMePS AONs targeting ISS-N1 to promote exon 7 inclusion in human fibroblasts and mouse brain	[92,93,94]
			Intrathecal injection of nusinersen to increase exon 7 inclusion in patients	[95,96,97,98,99,100]
			Splice switching and lncRNA-targeting AONs to promote inclusion of exon 7 in patient-derived cells and mouse brain	[102]
			Trans-splicing-mediated insertion of exon 7 in fibroblasts and SMAΔ7 mice	[145,146,147,148]
			CRISPR/Cas9-mediated disruption of intronic splicing silencers to enhance exon 7 inclusion in iPSC-derived motor neurons and mice	[153]
DMD	DMD	Formation of nonfunctional truncated dystrophin due to point mutations and frame-shifting deletions	2′OMePS- or PMO-mediated skipping of exon 51 in patients	[109,110,111,112,113,114,115]
			tcDNA-mediated exon skipping in mice	[116,117]
			Restoration of open reading frame by dual Cas9-mediated exon skipping in mdx mice	[155,156,157]
			dCas9-cytidine deaminase-mediated base editing to induce skipping of exon 50 and restore reading frame in iPSCs	[161]
FTDP-17	MAPT	Increased exon 10 inclusion	Trans-splicing to reverse aberrant exon 10 inclusion in mice	[142,143,144]
			dCas13 targeted to exon 10 splice sites on pre-mRNA to mediate exon exclusion in iPSCs-derived cortical neurons	[164]
Ataxia telangiectasia	ATM	Activation of cryptic splice sites	AMOs to mask cryptic splice sites and restore correct splicing in cell lines	[123,124]
Hutchinson-Gilford progeria syndrome	LMNA	Activation of an exonic cryptic donor splice site in exon 11	AMOs to block the recognition of cryptic splice sites in fibroblasts and mice	[128,129]
CF	CFTR	Three base-pair deletion in exon 10 causing deletion of F508	Correction of exon 10 by trans-splicing in epithelial cells and a xenograft model	[131,136]

Abbreviations: 2′OMePS: 2’-O-methyl-phosphorothioate RNA; AMO: Antisense morpholino oligonucleotide; AON: Antisense oligonucleotide; CF: cystic fibrosis; DMD: Duchenne muscular dystrophy; FTDP-17: Frontotemporal dementia with parkinsonism linked to chromosome 17; PMO: Phosphorodiamidate antisense morpholino oligonucleotide; SMA: Spinal muscular atrophy.