Table 1.

Summary of the present status of RNA-based therapies for the treatment of genodermatoses

RNA-based therapy	Mechanism of action	Delivery	Advantages	Limitations	Disease	Key references
AON	Induced skipping of mutated exon	Systemic Intradermal Topical	1. Systemic administration/multiple routes of administration 2. Natural regulation of gene expression kept 3. Advanced clinical developmen for other genetic diseases 4. Low toxicity and limited adverse events in clinical trials	1. Not suitable for all exons and genes 2. Effect mutation dependent and difficult to predict	EB	Goto et al. (2006)29 Turczynski et al. (2012)30 van den Akker et al. (2009)35
Trans-splicing	Exchange of an mRNA part, carrying a mutation, by its wild-type copy using the endogenous splicing machinery	Ex vivo (correction of skin cells and regrafting) Intraepidermal / Intradermal	1. Delivered transgene is shorter than full-length transcript (facilitates cloning and delivery) 2. Natural regulation of transgene expression 3. Applicable for dominantly inherited disorders	1. Safety issues from viral vector (stable integration is needed to achieve high trans-splicing efficiency) 2. Safety issues rom trans-splicing molecule (unspecific splice events)	EB	Koller et al. (2014) 55 Murauer et al. (2013)50
IVT mRNA-mediated transcript replacement therapy	Introduction of corrected mRNA transcripts to drive expression of wild-type proteins in vivo	Systemic Intradermal (Topical)	1. Correct post-translational modification 2. Multiple routes of administration 3. Non-integrative	1. Multiple administration 2. Delivery to the skin 3. Inability to regulate tissue-specific translation and protein expression levels	-	Kormann et al. (2011)68
IVT mRNA-mediated gene editing	In situ gene repair with IVT mRNA coding for optimized zinc finger, transcription activatorlike, or CRISPR-Cas9 nucleases together with a DNA template	Ex vivo (correction of skin cells and regrafting) Systemic Intradermal	1. Natural regulation of gene expression kept 2. Transient activity making it safer than vector-based approaches	1. Safety issues from nuclease activity and viral vector-based DNA template delivery 2. Delivery to the skin	EB	Osborn et al. (2013)70 Mahiny et al. (2015)71
Mutant gene/allele knockdown	Targeted degradation of mutant transcripts	Intradermal	1. Can be used for dominant disorders 2. Non-integrative 3. Natural regulation of gene expression kept	1. Painful drug administration 2. Effect mutation dependent and difficult to predict	Pachyonychia congenita, epidermolytic palmoplantar keratoderma, EB	Atkinson et al. (2011)77 Leachman et al. (2010)74 Leslie Pedrioli et al. (2012)75 Pendaries et al. (2012)78
Stop codon read-through	Induced read-through of PTCs	Oral	1. Systemic administration 2. Natural regulation of gene expression kept 3. Advanced clinical development for other genetic diseases	1. Toxicity 2. Only for PTCs 3. Increased translational inaccuracy	Xeroderma pigmentosum, EB	Cogan et al. (2014)89 Kuschal et al. (2013)90