About
I have obtained a master degree in Virology at Paris University/Pasteur Institute in 1998 and a PhD in Biochemistry at Paris University on the cloning of Synemin, a novel member of the intermediate filament family in 2001. I then joined the lab of Prof. Alain Hovnanian at the Wellcome Trust for Human Genetics in Oxford to initiate the project of ex vivo gene therapy for recessive dystrophic epidermolysis bullosa (RDEB). During this period, I visited the laboratory of Prof. Yann Barandon at EPFL in Lausanne, where I improved my knowledge on epidermal stem cells and graft of cultured epithelial sheets on nude mice. I have produced several retro-and lentiviral vectors expressing COL7A1, the defective gene in RDEB in order to achieve efficient gene transfer on primary human keratinocytes and fibroblasts. I also work on tissue-engineering in order to produce human skin equivalents suitable for long-term grafting and demonstration of efficacy of the gene therapy approach. This work has paved the way for the development of a clinical trial for RDEB sponsored by INSERM aiming at testing the safety and efficacy of an ex vivo gene therapy based on autologous graft of reconstructed skin made of keratinocytes and fibroblasts corrected with a SIN retroviral vector encoding the COL7A1 cDNA.
I have obtained a permanent researcher position at INSERM in France in 2010, and continue to develop therapeutic approaches for RDEB, including cell therapy for RDEB using bone-marrow derived mesenchymal stromal cells (MSCs) and the development of splice modulation strategies for RDEB, based on the delivery of antisense oligonucleotides (ASOs). Since 2014, I am working at the Imagine Institute where my main interests are to improve molecular diagnosis of genetic skin disorders, to better understand the pathophysiology of genetic skin disorders and to develop therapeutic approaches for Epidermolysis Bullosa. I have supervised the work of four PhD students on the development of splice modulation approaches for RDEB and on the potential of mesenchymal stromal cells for the treatment of RDEB. I have obtained my HDR in 2024. I am an elected member of the French Society of Gene and Cell Therapy since 2018.
Scientific project
Since 25 years, I study the molecular basis and pathophysiology of epidermolysis bullosa (EB), with a particular focus on Dystrophic EB (DEB) and EB simplex (EBS) forms, and I am developing various therapeutic approaches for these diseases. Hereditary epidermolysis bullosa (EB) is a group of genodermatoses transmitted in an autosomal dominant or recessive manner. EB patients suffer from fragility of the skin and mucous membranes leading to the formation of blisters and erosions. Among the four recognized EB subtypes, recessive dystrophic EB (RDEB) and junctional EB (JEB) are the most severe forms.
I am now developing 4 principal projects at different stages of development
1- An ex vivo gene therapy for recessive DEB (RDEB) using safe retroviral vectors. This proof-of-concept study led to the development of the EBGRAFT phase I/II clinical trial aiming at grafting autologous gene corrected skin equivalent in RDEB patients. The PI of this study is the Prof. Alain Hovnanian and I am the scientific director of the study. The clinical trial was sponsored by INSERM and financed by Cure EB. An extension of this clinical study is planned for 2027, sponsored by EB Therapeutics.
2- A targeted exon-skipping approach using in vivo delivery of small antisense oligonucleotides (ASOs) enabling restoration of the collagen 7 (C7) protein at the dermo-epidermal junction. ASOs are designed to induce targeted skipping of exon 73 of COL7A1, carrying recurrent recessive and dominant loss-of-function variants. Conjugated ASOs are injected I.V and are able to restore C7 expression and function at the dermal epidermal junction. This ongoing project aims at initiating a phase I/II clinical trial in 2028, sponsored and funded by EB therapeutics. I am the PI of the study.
3- An RNA interference approach for dominant forms of EBS aiming at selectively knock-down mutant alleles of KRT5 and KRT14. I have designed silencing RNA (siRNA) to specifically degrade mutated KRT5 or KRT14 transcripts carrying recurrent dominant variants in in vitro models. Several modes of administration of the siRNA will be tested in skin equivalent models in vivo, including local injection (subcutaneous injections, microneedles) or systemic delivery of naked, peptide-conjugated or LNP-formulated siRNAs, in order to achieve the highest efficiency. This project is funded by RNAderm and Cure EB. I am the PI of the study.
4- A strategy using small molecules aiming at improving nonsense readthrough. Nonsense variants usually result in severe forms of RDEB and JEB. There is therefore a major interest to target this specific type of deleterious variants. Previous studies have shown that gentamicin allows re-expression of functional type VII (C7) or laminin 332 proteins, but efficacy is contrasted among patients and gentamicin is known to induce nephrotoxicity and ototoxicity in the long-term and/or at high dose. The aim of this work is to enhance nonsense variants readthrough using small molecules targeting key actors of the process. I am the PI of this study funded by EBRP.
2021Journal (source)Nat Commun