Ex vivo gene modification therapy for genetic skin diseases—recent advances in gene modification technologies and delivery

Abstract

Genetic skin diseases, also known as genodermatoses, are inherited disorders affecting skin and constitute a large and heterogeneous group of diseases. While genodermatoses are rare with the prevalence rate of less than 1 in 50,000 – 200,000, they frequently occur at birth or early in life and are generally chronic, severe, and could be life‐threatening. The quality of life of patients and their families are severely compromised by the negative psychosocial impact of disease, physical manifestations, and the lack or loss of autonomy. Currently, there are no curative treatments for these conditions. Ex vivo gene modification therapy that involves modification or correction of mutant genes in patients’ cells in vitro and then transplanted back to patients to restore functional gene expression has being developed for genodermatoses. In this review, the ex vivo gene modification therapy strategies for genodermatoses are reviewed, focusing on current advances in gene modification and correction in patients’ cells and delivery of genetically modified cells to patients with discussions on gene therapy trials which have been performed in this area.

Challenges in Treating Genodermatoses: New Therapies at the Horizon

“…Similar projects have already been initiated for other conditions, including NS (Di et al, 2011) (Di et al, 2019) (for a review see (Ain et al, 2021) (Jayarajan et al, 2021)), porphyrias (Bustad et al, 2021), and DEB (Eichstadt et al, 2019). For the latter, experiments in engineered epidermal-dermal skin substitutes suggest that expression of the COL7A1 gene in both keratinocytes and fibroblasts is most likely necessary so as to produce structurally normal anchoring fibrils.…”

“…This agent has also been employed with success in a patient with NS ( Volc et al, 2020 ), and in another patient exhibiting a biallelic mutation in desmoplakin that manifested as ichthyosis ( Paller et al, 2018 ). Different case reports and small series have already been published focussing on Il-17 inhibitors such as sekukinumab ( Blanchard and Prose, 2020 ; Luchsinger et al, 2020 ; Barbieux et al, 2021 ) in NS, although sustained improvement could not be obtained in one patient. Given that, after this treatment, a Th2 signature remained ( Barbieux et al, 2021 ), using dupilumab, a blocker of the IL-4 receptor’s alpha-chain, thereby blocking Il-4 and Il-13 cytokines, could be another target for some NS patients, as it has already been tested with encouraging results ( Andreasen et al, 2020 ; Steuer and Cohen, 2020 ; Süßmuth et al, 2021 ).…”

The Potential of CRISPR-Guided Therapies in the Dermatology Clinic

“…Finally, most CRISPR-mediated gene therapy has focused on ex vivo treatment, namely editing of stem cells outside the body and subsequent reintroduction of corrected cells back into patients. Although this strategy has been done to edit human epidermal stem cells or induce pluripotent stem cells from patients ( Jayarajan et al., 2021 ) and successfully regraft corrected cells into mice, in vivo editing directly on the skin has been limited to a modicum of studies. Furthermore, gene editing of stem cells in vivo would target both stem and differentiated cells—this is likely not a limitation because stem cells will persist, and the differentiated skin cells will eventually die and slough off through the natural course of skin cell maturation.…”

“…Recently, several informative review articles in dermatology journals have focused on ex vivo DNA/gene-editing therapies for rare genodermatoses ( De Rosa et al., 2020 ; Jayarajan et al., 2021 ; March et al., 2018 ). In this study, we include both ex vivo and in vivo gene-editing applications in dermatology and further focus our attention on incorporating all classes of CRISPR nucleases—DNA and RNA targeting—into the repertoire of clinical tools available to the dermatologist.…”

Short-term Rho-associated kinase inhibitor treatment accelerates primary keratinocyte growth while preserving stem cell characteristics

“…Since epithelial sheet gene therapy requires genetically modified KSCs to produce a large number of gene-corrected keratinocytes for sheet formation, a low yield of holoclones/stem cells due to anoikis in freshly isolated keratinocytes unduly prolongs culture time of epidermal sheets. This leads to the premature exhaustion of KSC proliferative potential, the loss of KSC stemness, resulting in a short-lived epidermal sheet graft gene therapy that hinders its clinical application 5 .…”