Genetic skin diseases : from disease mechanism to therapy
- Hervé Bachelez
- Matthias Titeux
- Sabine Duchatelet
- Sonia Gaucher
- Araksya Izmiryan
- Claire Barbieux
- Olivier Gouin
- Maya Kaga
- Evgeniya Petrova
- Hélène Ragot
- David Woodley
- Nathalie Pironon
- Snaigune Miskinyté
- Yichen Wang
- Camille Berthault
- Pierre Bonnesoeur
- Mathilde Bonnet des Claustres
- Lucas Brusselle
- Florent Leturcq
- Clarisse Ganier
- Valérie Kayser Guelin
FURIO L. KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome PLoS Genet.2015 Sep 21. 11(9):e1005389
JACKOW J A Gene-corrected fibroblast therapy for recessive dystrophic epidermolysis bullosa using a SIN COL7A1 retroviral vector. J Invest Dermatol. 2016 Mar 16 pii : S0022-202X(16)30874-0
Turczynski S. Targeted exon skipping restores type VII collagen expression and anchoring fibril formation in an in vivo RDEB model. J Invest Dermatol. 2016 Dec;136(12):2387-2395.
Izmiryan A, Ex Vivo COL7A1 Correction for Recessive Dystrophic Epidermolysis Bullosa Using CRISPR/Cas9 and Homology-Directed Repair. Mol Ther Nucleic Acids. 2018 Sep 7;12:554-567.
Ganier C, Intradermal Injection of Bone Marrow Mesenchymal Stromal Cells Corrects Recessive Dystrophic Epidermolysis Bullosa in a Xenograft Model. J Invest Dermatol. 2018 Jul 11. pii: S0022-202X(18)31965-1
Genetic skin diseases : from disease mechanism to therapy
The skin forms a mechanical and immune barrier that is essential for body survival. Our team investigates several severe genetic skin diseases of children and adults in which these protective functions are drastically altered. These include rare, monogenic and orphan diseases, whose genes have been identified by our group: dystrophic epidermolysis bullosa, Netherton syndrome, Darier disease, Hailey-Hailey disease, but also frequent and polygenic inflammatory skin diseases such as Hidradenitis suppurativa and psoriasis. Our projects aim at better understanding the molecular mechanisms involved in these diseases, at identifying factors responsible for their phenotypic variability in order to develop new therapeutic strategies using gene and cell therapy, protein replacement, small molecules and/or pharmacological approaches.
Biotherapies, modifiers genes and mouse models for dystrophic epidermolysis bullosa (DEB)
We are implementing a first Phase I/II ex vivo gene therapy trial for recessive DEB using reconstructed autologous grafts genetically corrected with a secure, self-inactivating (SIN) retroviral vector expressing type VII collagen (orphan drug). This first in man clinical trial will be essential to assess the safety, efficacy and potential of the approach. Other approaches developed by the team include homologous recombination using CRISP/Cas9 in iPSCells, exon skipping for which we have generated a COL7A1 humanized mouse, nonsense reading through using aminoglycosides, genetically modified fibroblasts and bone marrow derived mesenchymal stem cells (MSC) in a xenograft murine model using human RDEB skin equivalents. A viable knock in murine model for RDEB carrying a homozygous hypomorphic Col7a1 mutation has been generated and extensively studied. This model has brought further insights into the development of fibrosis and provides a new in vivo model for therapeutic approaches. Transcriptomic and proteomic approaches aiming at identifying modifier genes and biological pathways involved in disease severity and in the development of squamous cell carcinomas in DEB are being pursued.
Netherton syndrome (NS): allergy by epidermal proteases dysregulation
We have characterized the biological cascade leading to skin inflammation, allergy and abnormal desquamation in NS. The cascade involves unopposed kallikrein (KLK) 5 (KLK5), KLK7 and KLK14 activities as a result of defective inhibition by LEKTI, leading to protease-activated receptor 2 (PAR2) activation, thymic stromal lymphopoietin (TSLP) and the production of pro-inflammatory cytokines. KLK5 is a major therapeutic target, which activates pro-KLK7 and pro-KLK14. In the context of industrial and academic collaborations, we are testing highly potent and specific KLK5 and KLK7 inhibitors in in vivo models. Biotherapy approaches aiming at blocking pro-inflammatory cytokines overexpressed in NS are also being considered. The team has developed several murine models, including a transgenic mouse overexpressing human KLK5, a viable conditional Spink5-/- mouse which allows systemic and/or topical treatment, and a double-knock out (Spink5-/-xKlk5-/-) murine model, which have confirmed the roles of klk5 and klk7 in NS pathogenesis and are useful models for drug testing.
Darier disease (DD), a disease model of abnormal calcium homeostasis
We previously identified ATP2A2 (encoding SERCA2, a calcium pump of the endoplasmic reticulum (ER)) as the defective gene in Darier disease. We have recently shown that loss of calcium transport leads to ER stress and abnormal trafficking of intercellular adhesion molecules. We have further shown that inhibition of ER stress with pharmacological agents leads to relocalization of E-cadherin and desmosomal components to the plasma membrane, indicating that these agents have a therapeutic potential. We have also recently identified different biological cascades involved in abnormal differentiation and skin inflammation which could guide new therapeutic approaches.
The team develops exome sequencing approaches to identify new genes for severe monogenic or polygenic skin diseases. These include rare keratinizing and inflammatory disorders such as Olmsted syndrome for which we have recently identified a new defective gene, severe ichthyosiform erythroderma, and frequent diseases such as hidradenitis suppurativa and psoriasis. Functional studies of identified genes are being developed in order to better understand the pathogenesis of these disorders, to disclose biological cascades involved and to identify therapeutic targets.