The MCDS-Therapy project

MCDS-Therapy is a collaboration of 11 partners from across the globe, all working together to repurpose carbamazepine to treat MCDS. We plan to develop a low-cost treatment that will alleviate the pain and bone malformations commonly experienced by patients. We are working closely with patients to do so. The project has been funded by the European Union’s Horizon 2020 Research and Innovation programme.

History of MCDS research

Type X collagen, a protein encoded by the COL10A1 gene, was first described in 1985 by researchers at Manchester University. Mutations in this gene were subsequently shown to cause the rare skeletal disease, metaphyseal chondrodysplasia type Schmid (MCDS) by several research groups across the world.

Since 1993, over 50 different mutations in COL10A1 have been identified globally. It has only been in the last decade that considerable progress has been made in identifying the underlying disease mechanism of MCDS. This progress has mainly been driven by the creation of genetically relevant mouse models of the condition.

MCDS-Therapy consortium members have been at the forefront of these discoveries. Their work has consistently demonstrated that mutant type-X collagen proteins misfold when they are produced and become trapped in a part of the cell called the endoplasmic reticulum (ER). This causes ER stress, which has been shown to cause the characteristic problems of MCDS.

Based on this knowledge, using drugs that can alleviate ER stress has the potential to ease the symptoms of MCDS in a relatively straightforward manner. Other therapeutic options, such as restoring the collagen matrix in the bone or directly correcting the mutation, would require much more expensive and timely treatment development.

  • 1984

    Discovery of type X collagen protein.

    Reference – Kielty et al., 1985

  • 1993-94

    Identification of COL10A1 mutations in MCDS.

    Reference – Wallis et al., 1994

  • 2005-2009

    Generation and phenotyping (identifying the characteristics) of genetically relevant mouse models.

    EU contribution  – The EuroGrow project, funded by the EU, supported this work.
    Reference – Rajpar et al., 2009

  • 2005-2009

    Identification of ER stress as core disease mechanism in MCDS and other genetic skeletal diseases (GSDs).

    EU contribution  – The EuroGrow project, funded by the EU, supported this work.
    Reference – Rajpar et al., 2009 and Cameron et al., 2011

  • 2015-2017

    Pre-clinical studies using CBZ

    EU contribution – The SYBIL project, funded by the EU, supported this work.
    Reference – Mullen et al., 2017

  • 2018

    MCDS-Therapy begins

    EU contribution – Horizon 2020, funded by the EU, is supporting this work.

How will the clinical trial work?

A clinical trial aims to provide the necessary evidence that proves a new treatment is both safe and effective for patients. To do so, patients who are treated with the drug must be compared to those who are not to identify the effect of the treatment.

In most trials, comparing patients who are on the drug to those who are off it requires a placebo. A placebo is a blank pill given to some patients, which does not contain the treatment. This approach allows there to be an untreated (control) group without the patients or researchers knowing who is being treated and who is not. This ensures that there is no bias when assessing the effect of the treatment.

When working with an ultra-rare bone disease like MCDS, small patient populations can make this type of trial design hard to achieve. When planning our clinical trial, the MCDS-Therapy team received guidance from the European Medicines Agency (the European organisation that approves new medicines for use, also known as the EMA). The EMA has approved a very different design for MCDS-Therapy.

Patients enrolled in our trial will first be monitored for a period of time with no treatment. This will create a set of baseline data that tells us how MCDS is affecting them. The baseline data will act as our control in the trial. After baseline data is collected, patients will be prescribed carbamazepine (CBZ) for 12 months to monitor and measure the effect CBZ has on treating MCDS.

Where will the trial be conducted?

As MCDS is a very rare condition, we will be recruiting patients from around the world for our clinical trial. The first patients will be recruited in the UK by both Newcastle-upon-Tyne Hospitals NHS Foundation Trust and the Evelina London Children’s Hospital (part of Guy’s and St Thomas’ NHS Foundation Trust). Recruitment will then be expanded to include:

Murdoch Children’s Research Institute logo

What is the timeline for the trial?

Our clinical trial began in 2019/2020 and is currently progressing through the following stages:

Stage 1 (UK participants only) as per the current protocol v8.0 consists of:

  • 12 months Baseline Observation
  • 12 months Dose Titration & Tolerability
  • 12 month Treatment phase + additional optional 12 months of treatment for eligible participants

Stage 2 (UK, Europe & International sites) as per the current protocol v8.0 consists of:

  • 6 months Baseline Observation
  • 12 month Treatment phase

What other work is being done?

Alongside the clinical trial, a number of other projects are being completed to ensure that the drug carbamazepine can be accessed by patients if the trial proves successful.

Biomarker development – A biomarker is a biological signal, often a chemical produced in the body, which can be used to monitor the body’s processes or the effect of a drug on a disease.
There are currently no biomarkers available for MCDS. A lack of biomarkers makes it significantly harder to measure the effect of a treatment on MCDS or to identify different variations of the disease, which are needed to tailor treatments to individual patients. To learn more about biomarkers, read our blog by Professor Mike Briggs, who is the Coordinator of MCDS-Therapy!

As part of the MCDS-Therapy project, Sciomics will be working to identify new biomarkers for the condition. The team at the University Medical Centre Freiburg will be simultaneously working to develop a new model system of human-stem-cell-derived MCDS cells, which can be used to help test these biomarkers.

Health Economics – Health economics is the study of the value of healthcare. It primarily aims to determine the cost-effectiveness of health interventions, such as treatments, by comparing the overall cost to society of a treatment to the overall benefit to society of treating that condition. Health economics helps governments decide which expensive treatments should be financed and delivered to patients.

As part of the MCDS-Therapy project, we will be working to understand the financial cost of MCDS to patients, the healthcare system and society. We want to provide evidence that treating the condition with carbamazepine (if proved to be effective in the clinical trial) is cost-effective. If you’d like to learn more about health economics, view our blog ‘Health economics: what is it and why bother?’ Express your interest in taking the Health Economic team’s quick survey to help improve the future of rare bone disease and skeletal dysplasia treatment and management!

Building the MCDS community – A rare disease diagnosis can be an isolating and devastating experience. Many patients struggle to find doctors who understand their condition and treatment needs. Some may never meet another with the same condition.

As part of the MCDS-Therapy project, we aim to work with patients to ensure that both the treatment and the clinical trial work for them. We also want to connect these individuals to help break the isolation felt and amplify their voices to ensure that it’s heard beyond the project. If you’d like to learn of any updates and opportunities for you to engage in upcoming projects or research, subscribe to our Skeletal Dysplasia Community Newsletter!