A promising drug for treating a debilitating genetic cartilage disorder is about to enter clinical trials in Australia. While preclinical results to date have been encouraging, exactly how the drug works remains a mystery.

Professor John Bateman from Murdoch Children’s Research Institute in Melbourne aims to solve it. Running in parallel with the clinical trial in children with the condition, his research will use stem cells to understand what’s happening at a molecular level.

About 100 babies are born in Australia each year with genetic cartilage and bone disorders, which prevent the normal development and function of the skeleton.

“Like all genetic disorders, they’re individually rare, but as a group, they’re a significant clinical problem,” John says.

“They affect a person’s growth and the strength of their skeleton, can lead to osteoarthritis, and cause a great deal of life-long pain and suffering.”

With your support, the National Stem Cell Foundation of Australia wants to help fund John’s work, so that his findings can help progress the trial to the next phase, uncover the disease mechanisms, and identify other drug candidates.

The Foundation aims to provide $100,000 for the project, by matching, dollar for dollar, every public donation of $500 or more up to a total of $50,000. You can contribute via our website – just specify ‘CARTILAGE’ when prompted.

John’s study focuses on metaphyseal chondrodysplasia, Schmid type (MCDS), a bone and cartilage disease caused by a mutation in a gene for the protein—collagen 10— which helps cartilage becomes bone.

Some mutations reduce the amount of collagen 10 produced; others stop the collagen protein from folding into a compact form that can leave the cell. It gets stuck in the cell, triggering a stress response, ultimately leading to shorter and bowed bones, and hip angle issues and back problems.

John and his team screened a number of different compounds that stimulate the breakdown of aggregated collagen. The best of these happened to be the existing FDA-approved epilepsy drug Carbamazepine (CBZ).

“We’ve shown in mouse models that we could break down of this stuff that was becoming constipated in the cells by giving them CBZ. This largely overcame the cartilage and bone defects: the skeleton grew more normally,” John says.

Next year, Australian children with MCDS will undergo a CBZ treatment trial at MCRI led by Professor Ravi Savarirayan. A total of 30 patients are involved in the trial globally.

John will use stem cells to recreate each patient’s exact genetic mutation in the lab, using the CRISPR gene editing technology that has just won a 2020 Nobel Prize. By using unedited cells from the same stem cell line, he will have the perfect experimental control.

John will explore how the cells respond to the drug at different doses, and unravel the molecular pathways involved. His results can then be correlated with the clinical trial results—the real-life experiences of the patients.

“It is not possible to obtain cartilage biopsies from patients. But using stem cells with a patient’s mutations, recreating the disease in a dish, allows you to understand the molecular detail of how a drug works in a way that you can’t in a patient.”

“We will know what the disease mechanisms are, we will know how the drug works, and we will be able to understand the outcomes of the clinical trial better so that the next generation of treatments can be targeted much more precisely.”

John and Ravi expect that, if all goes well with the clinical trial and his parallel study, CBZ could become an approved treatment in the near future.

But what he really hopes for is that his research will turn up new, even better ways or better drugs to target the disease, and that these approaches will form the basis for the treatment of a suite of related disorders that have similar mechanisms.