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), 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.
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. 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]
The British Journal of Dermatology. 2022;186(4):609-619. © 2022 Blackwell Publishing