Serotonin is a bioactive amine produced in the body from the dietary amino acid tryptophan. Serotonin helps maintain normal physiology, but its dysregulation can be a causative and persistent contributor to disease. Altavant is developing peripherally-targeted inhibitors of serotonin biosynthesis to address the pathological effects of excessive serotonin signaling as potential treatments for a variety of conditions.
The CNS and peripheral serotonin systems are separated by the blood-brain barrier. Altavant’s lead compound, rodatristat ethyl, was designed to be restricted to the peripheral circulation so it can selectively reduce serotonin in peripheral tissues and avoid impacting serotonin production in the brain.
Serotonin’s Effect on PASMCs Leads to Vessel Remodeling in PAH
Platelet-derived serotonin and locally produced serotonin from both lung tissue and arterial endothelial cells have been shown to induce excessive growth of pulmonary-artery smooth muscle cells (PASMCs). The unchecked growth of PASMCs is a major driver of the pathology of PAH and contributes to the remodeling of pulmonary arteries, which dramatically reduce the diameter and flexibility of the arterial lumen. This causes increased strain on the right heart as it tries to pump blood through the narrowed pulmonary arteries.4 Read More
The role of serotonin in PAH is supported through multiple pre-clinical and clinical observations (MacLean MMR Pulm Circ. 2018). Of note, serotonin has been shown to promote pulmonary smooth muscle cell proliferation through multiple mechanisms, both receptor-mediated and receptor-independent. Serotonin’s broad activity at these multiple pathways may explain why neither serotonin transporter (SERT) inhibition nor subtype-specific serotonin receptor antagonists alone have been able to fully reverse the negative effects caused by excess local serotonin in PAH. A more complete targeting of the serotonin pathway via inhibition of peripheral serotonin and local production in diseased tissues may, however, address both receptor-mediated and receptor-independent mechanisms.
It has been shown in vitro that serotonin receptor antagonists and SERT inhibitors can reduce the growth of PASMCs (Eddahibi S. et al. JCI 2001; Wallace e. et al. Am J Respir Crit Care Med 2015). However, the use of narrowly targeted serotonin-receptor antagonists has not proven effective in treating PAH in humans because there are several serotonin receptors and serotonin has receptor-independent effects via serotonylation. Consequently, we anticipate that a broader effect on the serotonin pathway by inhibiting its biosynthesis will be more effective. We believe that rodatristat’s direct inhibition of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the production of serotonin, will result in a reduction in total peripheral serotonin sufficient to halt and perhaps even reverse serotonin-induced vascular remodeling in PAH.
Serotonin Implicated in Interstitial Lung Diseases including IPF and Sarcoidosis
Idiopathic pulmonary fibrosis (IPF) is a disease of ageing where lung tissue is replaced with fibrotic tissue.5 Serotonin can promote the production of the pro-fibrotic molecule TGF-β and is a key regulator of the wound-repair response.6 Platelets normally release serotonin upon recruitment to sites of tissue damage and inflammation. Normally this is a carefully orchestrated response, but in some cases the fibrotic process can persist unresolved, and myofibroblast function can be aberrantly maintained leading to pathological fibrosis as seen in IPF. Rodatristat may be able to prevent or reduce the pro-fibrotic effects of serotonin-driven TGF-β in IPF. Read More
Serotonin can also modulate the immune system for example by influencing the balance of T cell subsets and regulating macrophage gene expression (Wu H et al. Pharmacological Research 2018). This effect along with its effects on fibrosis may implicate serotonin in the pathogenesis of sarcoidosis, which involves an aberrant immune response. In sarcoidosis, the immune system overreacts to an unknown insult and forms granulomas that often become encased in fibrotic tissue. If this occurs in the lungs, sarcoidosis can cause pulmonary hypertension by compressing and restricting pulmonary arterial blood flow. Rodatristat may be able to address the underlying fibrotic effects of granuloma formation in the lungs of patients with sarcoidosis.
For more information on the pathways by which serotonin acts in PAH, download our whitepaper.
1. Matthes S. and Bader M. Trends Pharmacol Sci 2018 2. Berger M et al. Annu Rev Med 2009 3. Matthes S. and Bader M. Trends Pharmacol Sci 2018 4. Maclean MMR Pulm Circ 2018 5. Lopez-Ramirez C. et al. Medical Sciences 2018 6. Dolivo DM. et al. Cell Mol Life Sci 2018