Science of MCDS-Therapy

Science behind MCDS-Therapy

Over the last 20 years, remarkable progress has been made in identifying the underlying genetic defects in many skeletal disorders. Mutations in over 250 different genes, causing more than 400 unique characteristics of skeletal disease (known as phenotypes), have been identified, including MCDS.

The members of MCDS-Therapy have made many of these important discoveries; however, there are currently very few therapies to prevent, halt, or modify skeletal disease progression. MCDS-Therapy aims to change that for metaphyseal chondrodysplasia type Schmid.

What is MCDS?

MCDS, or metaphyseal chondrodysplasia type Schmid, is an ultra-rare inherited disorder. It leads to short stature with disproportionately short arms and legs (called short-limbed dwarfism), as well as curvature, or bowing, of the leg bones (known as genu varum). The ends of long bones and ribs can also flare outwards, and there may be hip deformities causing the thigh bone to be angled towards the centre of the body (known as coxa vara). These characteristics can lead to an impaired gait when walking that can make movement difficult, as well as pain in the legs and joints throughout life.

What causes MCDS?

MCDS is caused by an error in the body’s genetic code. The error is located on the COL10A1 gene which creates a protein known as collagen X – or collagen 10. This mutation is a dominant trait, meaning that only one of the two copies of an individual’s COL10A1 needs to be a mutant in order for them to develop MCDS. Consequently, if you have MCDS there is a 50% chance of passing it on to your child.

Collagen is a protein that is used to form the hard structure of bone. This means that to function, it needs to be moved outside of the cells and into the surrounding bony matrix. In MCDS, errors in the gene for collagen X mean that cells build the protein incorrectly. This causes the protein to get trapped inside the cell. Specifically, the protein gets trapped within a part of the cell known as the endoplasmic reticulum (or ER), which become stressed (ER stress). Over time this is very bad for the health of cells that produce a lot of collagen X. It stops the cells functioning in a normal way, and ultimately leads to cell death.

Collagen X is only produced at the ends of bones in the cartilage growth plate. This is where cartilage is turned into bone when bones are growing. The end portions of long bones are known as metaphyses, and are responsible for the first part of the name of metaphyseal chondrodysplasia. In MCDS patients, ER stress hampers the growth of the bones as the cells in the growth plate stop changing – also known as differentiating – from cartilage to bone. This causes the characteristics of the condition: shortened limbs, bowed long bones, and flaring of the metaphyses.

How do we know ER stress causes MCDS?

A simple experiment proved that ER stress was the underlying cause of the characteristics of MCDS. Scientists created ER stress in growth plate cells unaffected by MCDS by causing a different protein to misfold. This led to the same problems in bone growth, and the same MCDS characteristics in the tested mice. This clearly suggests that treating ER stress should treat MCDS.

How was carbamazepine identified?

After ER stress was identified as a primary cause of the characteristics of MCDS, a number of drugs that act to lower ER stress were identified. MCDS affected cells were treated with each of these drugs, allowing their impact on ER stress to be measured. Of all the drugs screened, carbamazepine caused the largest reduction in ER stress, suggested it could be repurposed to treat MCDS.

What is drug repurposing?

MCDS-Therapy is working to develop a new treatment for MCDS using a drug repurposing approach: but what is drug repurposing?

Drug repurposing is just like recycling. It is the process of finding new uses for old or existing drugs, allowing us to use them for a wider range of conditions and to benefit more patients. By taking advantage of our existing knowledge about these drugs, it is possible to develop repurposed treatments more quickly and more cheaply than conventional drug discovery, which makes it particularly attractive for rare diseases.

Members of the MCDS-Therapy team have identified carbamazepine, a drug that is used primarily in the treatment of epilepsy, as a potential treatment for MCDS.

What evidence supports the use of carbamazepine in MCDS?

Carbamazepine has been tested in a mouse model of MCDS, as well as in a cell system. MCDS mice exhibit a number of characteristics of the condition. They are generally shorter than unaffected mice, and have a curved and distorted pelvis. If you stain the cells of the growth plate of the long bones and view them under a microscope you can see that collagen X is retained within the cells, rather than moved into the external matrix.

When treated with carbamazepine, these mice show a dramatic change. Less collagen X is retained in the cells at the growth plate. This translates into mice that are much larger – only a little smaller than non-MCDS mice. Furthermore, their pelvis lacks any distortion, providing further evidence that carbamazepine can have a therapeutic effect on MCDS.

Finally, there are a number of historical cases where patients with skeletal dysplasias have coincidentally been treated for epilepsy with carbamazepine. In these instances the patients are reported to have shown increased rates of growth.

Why do we need a clinical trial?

While the existing evidence for the effect of carbamazepine on MCDS is encouraging, its effect on MCDS patients has never been properly assessed. A clinical trial will allow a rigorous scientific assessment of the benefits and risks of the drug to MCDS patients, so that fully informed decisions about its safe use can be made by doctors and patients. More specifically, a clinical trial will help to:

  • Assess the safety of using carbamazepine in MCDS patients – Are there any detrimental side effects? What dose will minimize any problems while maximising benefit? Are side effects more prevalent or problematic in a certain group of patients?
  • Assess the effect of carbamazepine on patients – Does treatment lessen patient pain? Does it reduce curvature of long bones? Does it accelerate the rate of bone growth? Does it improve patient quality of life?

What are the next steps?

MCDS-Therapy aims to deliver a clinical trial to answer these important questions. The trial is designed to allow all patients who take part to get access to the drug. The first stage will take place in the UK, where a number of patients will be enrolled and be assessed without treatment for a year. This will allow their normal levels of growth and pain to be assessed. This will then be used as a comparison to the same measures when treatment is provided, allowing the impact of the drug to be assessed.

You can learn more out the trial and project as a whole on our MCDS-Therapy project page. We will also release news and blog articles to give more information about the science of MCDS, and the progress of the trial.