5-HT2B Receptors In Fibrosis

Several diseases are caused by a process whereby normal healthy tissue is replaced by fibrotic tissue, leading to organ dysfunction, morbidity and mortality. These chronic disorders arise when fibroblasts after tissue injury differentiate into over-activated myofibroblasts, producing excessive amounts of extracellular matrix. Fibrotic disorders affect millions of patients but have limited, if any, treatment options.

Serotonin or 5-hydroxytryptamine (5-HT) is a well recognized stimulator of tissue fibrosis. Peripheral 5-HT is mainly produced by enterochromaffin cells and stored in platelets. Upon vascular damage, platelets become activated and release 5-HT, resulting in increased local concentrations. Such dysregulated 5-HT activity leads to fibrosis. Resent research has revealed that peripheral 5-HT2B receptors are upregulated in fibrotic tissue, studying e.g. dermal fibroblasts from systemic sclerosis patients. Activation of the 5-HT2B receptor on macrophages or fibroblasts results in myofibroblast differentiation and activation, increased TGF-β activity, excessive extracellular matrix synthesis and eventually fibrosis, which clearly demonstrates the pathogenic link.

AnaMar develops 5-HT2B receptor antagonists for the treatment of a broad range of fibrotic disorders. This new treatment approach targets the macrophage, the extracellular matrix producing myofibroblast and the TGF-β pathway, thereby preventing fibrosis. The compounds have shown potential to halt and reverse the progression of fibrosis in different tissues and could potentially be used as monotherapy or in combination treatments. The scientific concept has been validated in preclinical studies, where halted progression and reversal of fibrosis have been demonstrated in several fibrotic tissues. This implies utility, for example, in dermal, lung, liver and cardiac fibrosis.