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Combined cell and gene therapy for Epidermolysis Bullosa - 14 June 2022

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Speaker Professor Michele De Luca, Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, Modena, Italy

Title Combined cell and gene therapy for Epidermolysis Bullosa

Host Massimo Ganassi

 

Abstract LAMB3-dependent generalized Junctional Epidermolysis Bullosa (JEB) was targeted by transplantation of epidermal cultures originated from transgenic epidermal stem cells. We report life-saving regeneration of the entire epidermis on a seven-year-old JEB child suffering from a devastating form of JEB. The regenerated transgenic epidermis remained stable throughout the entire 6-year follow-up period and did not form blisters, even upon shear force. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew and produce short-lived progenitors that replenish terminally differentiated keratinocytes.

In studying the different behavior of JEB and COL7A1-dependent generalized Dystrophic EB (RDEB) cultures we discovered a pivotal role of YAP in sustaining human epidermal stem cells, which explains the progressive stem cell loss observed in JEB. Epidermal stem cell depletion of primary JEB keratinocytes is due to perturbation of the YAP/TAZ pathway and consequent alteration of the expression of FOXM1. This pathway is not altered in RDEB, explaining the different behavior of transgenic RDEB cells vs transgenic JEB cells. This notion imposes the development of a different gene correction strategy to successfully tackle RDEB.


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