Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis

Abstract

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

Keywords: Cell therapy; Epidermolysis bullosa; Gene therapy; Ichthyosis; Rare disease.

Fig. 1

In vivo gene therapy for epidermolysis bullosa and ichthyosis. In vivo gene therapy approaches for epidermolysis bullosa and ichthyosis, including gene replacement and gene editing, can be delivered by both viral and nonviral vectors. Beremagene Geperpavec (a gene therapy indicated for the treatment of wounds in patients with recessive dystrophic epidermolysis bullosa with mutations in the gene encoding the type VII collagen alpha-1(VII) chain [COL7A1]) and KB105 (an investigational gene therapy for lamellar ichthyosis caused by mutations in the transglutaminase 1 gene [TGM1]) both use a herpes simplex type 1 viral vector for the delivery of COL7A1 and TGM1, respectively. Illustration was created with BioRender.com

Fig. 2

Ex vivo cell therapy for the treatment of epidermolysis bullosa. Ex vivo cell therapy approaches, which have only been described for epidermolysis bullosa so far, require a primary specimen to be collected from a patient. These primary specimens are then genetically manipulated (sometimes alongside reprogramming) to either replace the pathogenic COL7A1 allele or correct the endogenous pathogenic variant using the CRISPR/Cas9 gene-editing technology. Corrected primary specimens can be transplanted directly onto the patient or grafted by epidermal sheets. Genetically corrected induced pluripotent stem cells can be differentiated into fibroblasts and keratinocytes and similarly, be grafted directly onto patients. Illustration was created with BioRender.com