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Targeting Notch signalling by the gamma-secretase inhibitor PF-03084014 to counteract fibrosis progression in recessive dystrophic epidermolysis bullosa (Condorelli 1)

Project lead Dr Angelo Giuseppe Condorelli
Organisation Bambino Gesù Children’s Hospital, IRCCS, Rome, ITALY
Project budget EUR 248.500
Start date / Duration 30. Aug 2023 / 36 months
Funder(s) / Co-Funder(s) DEBRA Austria, EB MSAP/EBEP Recommended
Research area Skin cancer & fibrosis, Symptom prevention & relief

Project details

Short lay summary

Despite research progress, no cure for RDEB is available as yet. However, the identification and characterization of novel disease-contributing factors have led to the therapeutic assessment of symptom-relieving molecules to contrast severe RDEB manifestations, including fibrosis. In this context, our laboratory findings identified the Notch signalling cascade as novel player in RDEB-associated fibrotic processes. In addition, we demonstrated that Notch inhibition by DAPT and PF-03084014 (nirogacestat), two compounds belonging to the family of g-secretase inhibitors, attenuates several fibrotic traits in patient fibroblasts (RDEB-FBs) such as the ability to contract a collagen matrix. Of note, PF-03084014 showed a greater efficacy in reducing fibrotic behaviour of RDEB-FBs as compared to DAPT. Prior to test the fibrosis-limiting potential of PF-03084014 in RDEB patients, its safety and efficacy need to be validated in an animal model of RDEB. This project aims at evaluating the therapeutic potential of PF-03084014 in RDEB mice.

Scientific summary

The main goal of this project is the evaluation of the anti-fibrotic effects and therapeutic potential of Notch pathway inhibition by the g-secretase inhibitor PF-03084014 in a well-established animal model of RDEB: the type VII collagen hypomorphic mouse. After weaning, RDEB mice will be treated with PF-03084014 for 12 weeks, according to a previously described intermittent schedule comprising a 1-week drug holiday every other week. The compound will be administered daily by mixing it into pasty food. Wild-type and RDEB mice treated with the vehicle (i.e. 0.5% methylcellulose) will serve as controls. Contextually to the treatment, the drug impact on fibrosis onset and maintenance will be monitored by evaluating the general health status (e.g. ability to feed, hair coat condition) and the overt fibrotic phenotype of RDEB mice. The assessment of digit length and digit fusion/loss will serve as primary indicator of disease progression/drug efficacy. At the end of treatment, the expression levels of several fibrotic (e.g. a-SMA, fibronectin 1, TGF-b1 pathway members) and pro-inflammatory markers (e.g. interleukin-6) will be investigated at microscopic and molecular level both in skin sections and “whole” skin RNA and protein lysates from the back and the forepaws of RDEB mice. In addition, the fibrosis-limiting effects of PF-03084014 will be explored in a selection of extracutaneous organs affected by fibrosis such as oesophagus and eye. Finally, we intend to further characterize PF-03084014 molecular targets, mechanisms of actions and impact on a selection of biological processes in fibroblasts and keratinocytes from RDEB patients as well as in two-dimension models and organotypic skin cultures of the above cell types.

Strategic relevance

The existing know-how derived from clinical studies aimed at evaluating the therapeutic potential of PF-03084014 (nirogacestat) in adult and paediatric patients affected with unresectable desmoid tumours represents a solid background to PF-03084014 future repurposing and potential applicability in RDEB. Moreover, the oral administration route of PF-03084014 and, in turn, its potential systemic effects represent further advantages of using PF-03084014 as an easy-to-handle strategy to counteract RDEB fibrosis. The successful implementation of the proposed studies on PF-03084014 will set the stage for the development of a clinical trial to assess its safety and efficacy in limiting fibrotic processes in RDEB patients.


Notch pathway
type VII collagen hypomorphic mouse
RDEB mouse
Condorelli 1
Bambino Gesù Chrildren's Hospital
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