Achondroplasia is easily recognized by short limbs that lead to dwarfism. It is not normally associated with life threatening conditions but does affect quality of life and can result in stenosis that cause debilitating neurological conditions. Using mice and iPS cells, CiRA Professor Noriyuki Tsumaki and his research team, in collaboration with Astellas Pharma Inc., reports a new candidate drug they call ASP5878 for the condition.

Achondroplasia is caused by mutations in the gene encoding the fibroblast growth factor receptor FGFR3. Mice deficient in this gene show bone overgrowth, suggesting the mutation causes FGFR3 hyper-activity. Thus, researchers have targeted drug candidates that primarily reduce the strength of the FGFR3 signal during bone growth, i.e. prior to adulthood.

"Because the number of patients with achondroplasia is small because the market is small and because the development of a new drug costs a lot, the progress of research in drug discovery for rare diseases such as achondroplasia has been limited," explains Tsumaki, whose research team is using iPS cell technology to develop cell therapies and drugs to treat cartilage diseases.

Currently, the most promising treatment is vosoritide. Vosoritide is an analogue of C-type natriuretic peptide (CNP) and interacts with FGFR signaling but also requires daily injections. In contrast, ASP5878 can be taken orally and directly inhibits FGFR signaling.

"Several drugs that inhibit FGFRs are currently under development as anti-cancer drugs. Since there is an abundance of patient information on these drugs, we decided to explore whether they could be repurposed for achondroplasia," he continued.

To test the benefits of ASP5878, the study first applied it to mice with a mutation in the Fgfr3 gene. Femurs and tibiae grew in mice. Growth plate cartilage also grew in the two bones.

"We consider that growth in growth plate cartilage accounts for the capacity for more bone growth in the ASP5878-treated group. Cell behavior in growth plate cartilage requires more study in the future," says Tomonori Ozaki, an orthopedic surgeon and first author of the study.

To test the effects on humans, the researchers reprogrammed achondroplasia patient cells into iPS cells and prepared chondrocytes from them. Unlike reprogrammed healthy cells, reprogrammed patient cells do not show cartilaginous properties under this treatment. However, this deficiency was resolved if ASP5878 was added to the differentiation protocol.

Clinical trials for ASP5878 were conducted on adults suffering from one of several types of cancers including those affecting the liver, lung and urethra, providing information on its side effects and safe dosage levels. At the same time, exclusive study is needed on the patient group who would use the drug for achondroplasia, namely children and juveniles.

Furthermore, although the mouse experiments show that the effectiveness of ASP5878 is less than vosoritide, researchers and clinicians like Tsumaki expect that patients are more likely to follow a regimen in which a drug that can be taken orally than a regimen that requires daily injections.

"We need more data on its effects and toxicity on juveniles in preclinical tests, but this is a starting point to repurpose drugs for cartilage diseases," he says.

• doi: 10.1038/s41598-020-77345-y