Regenerative
Antibody blocks bone growth in soft tissue in FOP mouse study
By Life and Health Today Staff, . Life and Health Today.
Fibrodysplasia ossificans progressiva, known as FOP, is a rare genetic disorder in which soft tissues such as muscle and connective tissue gradually turn to bone, progressively locking the body in place. Researchers publishing in Molecular Therapy, the journal of the American Society of Gene Therapy, have identified a protein called CCN2, also known as CTGF or connective tissue growth factor, as a critical driver of that process, and shown that blocking it reduced abnormal bone formation in mice carrying the FOP mutation.
FOP is caused by a mutation in a gene called ACVR1, specifically the variant designated R206H. The study focused on mesenchymal progenitors, a type of stem-like cell in connective tissue that can develop into bone, cartilage or fat. According to the paper, cells carrying the ACVR1 mutation were unusually resistant to apoptosis, the normal process by which damaged or surplus cells destroy themselves. The researchers proposed that this resistance allows the mutant cells to accumulate during FOP flare-ups, the episodes of inflammation that trigger new bone deposits.
When the team analysed the gene activity of these mutant cells, they found elevated levels of CCN2 alongside disrupted genes linked to fibrosis, the scarring of tissue, and to bone formation. They traced CCN2's elevated production to a cooperative interaction between two signalling molecules, SMAD1 and YAP-TEAD, acting together at the section of DNA that controls CCN2 output.
To test whether blocking CCN2 could interrupt the process, the researchers used pamrevlumab, an antibody drug that neutralises CCN2. In mutant cells in the laboratory, pamrevlumab blocked the early steps by which those cells commit to becoming bone or cartilage. It also partially suppressed the activity of two signalling pathways, one driven by a protein called Activin A and one by the TGF-beta family, both of which are implicated in FOP's progression. In a mouse model of FOP, pamrevlumab significantly reduced ectopic bone formation, meaning bone growing where it should not.
The paper describes these findings as identifying CCN2 as a potential therapeutic target for FOP and for other conditions involving pathological ossification, the abnormal hardening of soft tissue into bone.
Several limits apply before this can be read as evidence of a treatment. The cell work was done in laboratory cultures, and the animal work was in mice engineered to carry the FOP mutation. Neither establishes that pamrevlumab would be safe or effective in people with FOP. Pamrevlumab has been studied in human trials for other conditions, including a lung-scarring disease called idiopathic pulmonary fibrosis, but the Molecular Therapy paper does not report any human FOP data. The authors describe the mouse results as a partial suppression of bone formation, not an elimination of it, and the paper does not quantify the degree of reduction in terms a reader can directly compare to clinical outcomes.
FOP affects an estimated one in two million people worldwide, which means large randomised trials are difficult to run. The open question is whether the CCN2 pathway plays the same central role in human FOP flare-ups that it appears to play in this mouse model, and whether pamrevlumab reaches the relevant tissues at doses that are tolerable. Those questions would require human trials to answer. Anyone with FOP or a family member with the condition should discuss what trials or treatments may be available with a specialist who knows their history.
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