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 Are the Barriers to Successful Clinical Translation of ex Vivo Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa?

Firstly, COL7A1, located on human chromosome 3p21, is a large gene: it is composed of 118 exons and the gene spans over 32 kb, which generates a complementary DNA (cDNA) of 8·9 kb, encoding a protein of 2944 amino acids (over twice the size of LAMB3, a gene encoding laminin subunit beta-3, another BMZ protein mutated in JEB, and which comprises 23 exons and generates a cDNA of 3·5 kb).[29–31] The size of COL7A1 cDNA borders on the maximum cargo capacity of most viral vectors used for gene therapy (8–9 kb), the consequence of which is a limitation on the efficiency by which the transgene is successfully incorporated into the host genome ex vivo (transduction efficiency).

Secondly, there is a risk of gene transfer vectors affecting the physiological genomic organization of transduced cells, leading to activation of proto-oncogenes and causing malignant transformation (insertional mutagenesis),[32] which when translated to patients could cause serious adverse events such as leukaemia.[33–35] However, this risk has been mitigated by the development of safer integrating vector systems – self-inactivating (SIN) RVs or LVs – in which virulence factors and the enhancer/promoter regions are deleted.[32]

Thirdly, there is a theoretical risk of autoimmune reactions against the newly synthesized C7 protein, causing an acquired form of EB (EB acquisita) with more generalized blistering.[36] Despite the theoretical risk, there are no reported cases to date of autoimmune reactions or other serious adverse reactions in patients with RDEB or JEB who have received gene therapy.[31,37–41]

Lastly, the mode of administration of gene-modified cells to patients also poses challenges and risk. For instance, grafting methods risk engraftment failure, infection and the need for general anaesthesia, and being labour-intensive, whereas intradermal injections can cause intolerable pain especially in chronic wounds, which often have a degree of scarring and fibrosis as complications of RDEB.[25,41]