Product Candidate
Thymosin Beta-4 in COVID-19–Related Mechanisms
Thymosin beta-4 (Tβ4) has been discussed as a potential modulator of pathways that may be relevant in severe COVID-19, particularly fibrinolysis and inflammatory responses. One proposed mechanism involves prevention of actin binding to fibrin, a major component of blood clots. By influencing actin–fibrin interactions, Tβ4 may facilitate fibrinolysis, the enzymatic breakdown of fibrin in blood clots, and thereby modulate thrombotic processes that contribute to morbidity in severe COVID-19 (1).
In patients with COVID-19, microvascular thrombosis and dysregulated coagulation have been associated with organ damage and adverse outcomes. At the same time, a mechanistic model has highlighted the role of a renin–angiotensin system–mediated “bradykinin storm,” in which elevated bradykinin levels may drive vascular dilation, increased vascular permeability, hypotension, pain, and tissue swelling (1). In severe cases, such mechanisms are thought to contribute to fluid leakage into the lungs, accumulation of hyaluronic acid, impaired gas exchange, and many of the serious respiratory manifestations observed in COVID-19.
An additional hypothesis concerns sex differences in COVID-19 outcomes. The gene encoding Tβ4 resides on the X chromosome. Since women carry two X chromosomes and men one, differential expression of X-linked genes has been suggested as one of several possible contributors to the higher COVID-19 mortality observed in men compared with women. Within this framework, relatively higher Tβ4 levels have been proposed as a factor that could, in theory, influence outcomes, although this remains to be tested directly (1).
Tβ4 has been reported to down-regulate inflammatory chemokines and cytokines, modulate pro-inflammatory processes such as those associated with bradykinin signalling, increase fibrinolysis, and support tissue repair in organs commonly affected in severe COVID-19, including the heart, lungs, and kidneys. Levels of Tβ4 appear to decline with age in blood, tears, and saliva (1), which has prompted interest in whether pharmacological Tβ4 supplementation could be explored as a future strategy in high-risk populations.
At present, these concepts are largely based on mechanistic models, experimental data, and indirect clinical observations. Tβ4 remains an investigational candidate in this setting, and rigorous preclinical and clinical studies are required to determine whether modulation of these pathways translates into clinical benefit in COVID-19 or related conditions.
Reference
- Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, Mast AE, Justice A, Aronow B, Jacobson D. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Elife 2020;9:e59177. doi:10.7554/eLife.59177.