Repurposing of carbamazepine for treatment of skeletal dysplasia


Genetic skeletal diseases (GSDs) are an extremely diverse and complex group of rare genetic diseases that affect the development the skeleton. There are more than 450 unique and well-characterised phenotypes that range in severity from relatively mild to severe and lethal forms. Although individually rare, as a group of related genetic skeletal diseases, GSDs have an overall prevalence of at least 1 per 4,000 children, which extrapolates to a minimum of 225,000 people in the 27 member states and candidate countries of the EU. This burden in pain and disability leads to poor quality of life and high healthcare costs. Metaphyseal chondrodysplasia, type Schmid (MCDS) results from mutations in collagen X and affects <1/100,000 of the population. Mutant collagen X molecules miss-fold during synthesis and are retained within the endoplasmic reticulum (ER) of hypertrophic chondrocytes, thereby causing ER stress. Our extensive pre-clinical studies have shown that carbamazepine (CBZ) can alleviate ER stress caused by the expression of mutant collagen X and restore bone growth in a validated mouse model of MCDS. CBZ is an FDA approved drug used for the treatment of epilepsy and bipolar disorder and received orphan drug designation by the European Commission for the treatment of MCDS in September 2016. MCDS-Therapy is a 5-year collaborative project comprising world-renown clinical centres and SMEs to advance the repurposing of CBZ for MCDS (up to the Marketing Authorization Application dossier) through a multicentre and multinational (EU & AUS) clinical trial (Phase1, Phase2/3). MCDS-Therapy also encompasses biomarker development and health economics assessment studies to deliver by 2022 an innovative and affordable (CBZ already exists in a generic form) repurposed therapy for MCDS along with the diagnosis/prognosis tools to personalise the treatment strategy.

Project details

Unibo Team Leader: Francesco Paolucci

Unibo involved Department/s:
Dipartimento di Sociologia e Diritto dell'Economia

Newcastle University(United Kingdom)

Other Participants:
Universiteit Antwerpen (Belgium)
Sciomics Gmbh (Germany)
Inserm (France)
Istituto Ortopedico Rizzoli (Italy)
Guys And St Thomas' Nhs Foundation Trust (United Kingdom)
Universitätsklinikum Freiburg (Germany)
Murdoch Childrens Research Institute (Australia)
Finovatis (France)
Findacure Foundation (United Kingdom)

Third parties:
ALMA MATER STUDIORUM - Università di Bologna (Italy)

Total Eu Contribution: Euro (EUR) 5.697.390,50
Project Duration in months: 60
Start Date: 01/12/2017
End Date: 30/11/2022

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Good health and well-being This project contributes to the achievement of the Sustainable Development Goals of the UN 2030 Agenda.

UE flag This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 754825