2 Gene Therapy
Gene therapy for RDEB has been in development for more than a decade. In theory, replacing a non-functioning gene with a synthetic copy of a functional gene makes mechanistic sense but advancing to clinical trials has been beset with difficulties—efficiency, delivery, and safety concerns continue to require pre-clinical optimization. To date, there has only been one report of a clinical trial of gene therapy in EB and that involved grafting of LAMB3 gene-corrected keratinocytes in a patient with non-Herlitz junctional EB. For RDEB, ex vivo COL7A1 gene correction and grafting of keratinocyte sheets onto individuals with RDEB is in the early stage of a phase I trial at Stanford University, USA, although international efforts to launch similar clinical trials are ongoing in many other countries.
Another approach is to try to edit or correct mutant genomic sequences. Genomic editing utilizes the properties of engineered nucleases that produce targeted DNA double- strand breaks and activate cellular DNA repair mechanisms. The delivery of nucleases to target DNA-binding domains can be achieved via zinc-finger nucleases (ZFNs), transcription activator-like effector proteins (TALENs), or clustered regulatory interspaced short palindromic repeats (CRISPR)-based RNA-guided DNA endonucleases.[10,11] Genome editing technology has been investigated in RDEB. Notably, TALENs have been used to correct COL7A1 gene mutations in primary fibroblasts, findings that have exciting translational potential for patients.
Am J Clin Dermatol. 2014;15(1):1-6. © 2014 Adis Springer International Publishing AG