The Potential of Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa

K.S. Subramaniam; M.N. Antoniou; J.A. McGrath; S.M. Lwin


The British Journal of Dermatology. 2022;186(4):609-619. 

In This Article

What is Gene Therapy and What are the Principles Underlying Different Approaches of Gene Therapy?

Gene therapy involves the manipulation of cellular DNA or RNA to provide therapeutic benefit using various strategies. These include gene addition or supplementation and gene correction through RNA-based technologies or genome editing tools. These approaches may be used to modify cells either directly in vivo, or by ex vivo manipulation before administering to patients (Figure 1).

Figure 1.

Summary of in vivo and ex vivo gene therapy approaches for recessive dystrophic epidermolysis bullosa (RDEB). COL7A1, collagen type VII alpha 1 chain gene; iPSCs, induced pluripotent stem cells. Created using bioRENDER (

In vivo gene therapy involves direct delivery of the genetic therapeutic agent to the patient's tissues or target cells using viral or nonviral (e.g. synthetic polymer) vectors. Conversely, ex vivo gene therapy comprises genetic manipulation in the laboratory of patient cells, which are then expanded and administered back to the same patient (i.e. gene-modified autologous cells). The therapeutic genetic material (transgene) is then incorporated into the host cell genome via a process called transduction. Of the various viral vector delivery systems utilized in both forms of gene therapy, those commonly used to target skin include retroviruses (RVs), lentiviruses (LVs), herpes simplex viruses (HSVs), adenoviruses (AVs) and adeno-associated viruses (AAVs). Gene therapy does not include vaccines against infectious diseases.[20] Single-gene disorders, such as RDEB, are seen as primary targets for gene therapy.

The choice of gene therapy strategy in genodermatoses depends on the mode of inheritance and the nature of pathogenic mutations of a particular disorder. Given that most autosomal recessive skin disorders often result in loss of function, deficiency or absence of the wildtype protein, the addition of the functional wildtype copies of the mutant gene via viral or nonviral vectors should restore protein expression and function. Conversely, most dominant skin disorders typically exhibit heterozygous mutations whose defective protein adversely affects the normal, wildtype protein within the same cell, thereby blocking some aspects of its function (dominant-negative interference). Thus, therapeutic benefits of dominant disorders are best sought by ablation of the mutant allele while preserving the functional wildtype allele, through application of gene correction techniques using small interfering RNAs (siRNAs) or targeted genome editing endonucleases. Genome editing is also demonstrated, in preclinical stage, to be effective in recessive skin disorders with specific mutations to correct both affected alleles. However, the main advantage of the gene addition approach over gene correction is that it can be used to treat any patients with the same genetic defect, regardless of the type of mutation they harbour.