EP-4739314-A1 - USE OF TRYPTOPHAN HYDROXYLASE 1 (TPH1) INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROSIS

EP4739314A1EP 4739314 A1EP4739314 A1EP 4739314A1EP-4739314-A1

Abstract

Tryptophan (Trp) is one of the nine essential amino acids supplied by the diet, whose metabolism appears as a key metabolic gatekeeper of intestinal homeostasis, although its systemic effects, particularly on atherosclerosis, remain unknown. The inventors show that the high-fat diet (HFD) but not the high-cholesterol diet (HCD) increases intestinal indoleamine 2, 3-dioxygenase 1 (IDO) activity, the main enzyme involved in Trp catabolism in the gut, which shifts intestinal Trp metabolism from microbiota-produced indole metabolites and serotonin or 5-hydroxytryptamine (5-HT) production towards Kynurenine production. Most importantly the inventors showed that inhibition of tryptophan hydroxylase 1 (TpH1), markedly reduces intestinal 5-HT production and alleviates atherosclerosis as well as plaque inflammation. Accordingly, the present invention relates to the use of tryptophan hydroxylase 1 (TpH1) inhibitors for the treatment of atherosclerosis.

Inventors

TALEB, SORAYA
CHAJADINE, Mouna

Assignees

Institut National de la Santé et de la Recherche Médicale
Université Paris Cité

Dates

Publication Date: 20260513
Application Date: 20240704

Claims (5)

1. A method of treating atherosclerosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a tryptophan hydroxylase 1 (TpHl) inhibitor.
2. The method of claim 1 wherein the TPH1 inhibitor reduces the size of the atherosclerotic plaques.
3. The method of claim 1 or 2 that involves the local administration to the bowel of the TPH1 inhibitor.
4. The method of claim 3 wherein the TPH1 inhibitor is orally administered to the patient.
5. The method of claim 3 wherein the TPH1 inhibitor of the present invention is rectally administered to the patient.

Description

USE OF TRYPTOPHAN HYDROXYLASE 1 (TPH1) INHIBITORS FOR THE TREATMENT OF ATHEROSCLEROSIS FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular cardiovascular diseases. BACKGROUND OF THE INVENTION: The gut has become recognized as an important link between diet and cardiovascular diseases (CVDs), including atherosclerosis (Cainzos-Achirica et al. 2020). Particularly, the gut microbiota has been identified as a potential mediator that could impact atherosclerosis. Although evidence has been put forth to account for the relationship between gut inflammation and CVDs, little is known about the mechanisms whereby the intestine might contribute to atherosclerosis. Particularly, the gut metabolism could account for the links between local disruption of gut homeostasis and systemic development of atherosclerosis. Tryptophan (Trp) is one of the essential amino acids supplied by the diet, whose metabolism appears as a key metabolic gatekeeper of intestinal homeostasis. Trp is involved in various physiological processes and contributes to the maintenance of intestinal and systemic homeostasis in health and disease(Zc7a///c et al. 2013, Gao et al. 2018). In mice, dietary lack of Trp leads to impaired intestinal immunity and gut microbiota dysbiosis, which causes intestinal inflammation and diarrhea (Hashimoto et al. 2012). In humans, patients with intestinal bowel disease (IBD) exhibit disturbed tryptophan metabolism, likely due to altered gut microbiota (Lamas et al. 2016). However, despite the importance of intestinal Trp metabolism in gut homeostasis along with the ascertainment that intestinal inflammation is associated with CVD, the systemic impact of gut Trp metabolism on atherosclerosis is still unclear. Under homeostatic conditions, Trp catabolism in the intestine follows three pathways, which consist in the Kynurenine (Kyn) pathway mainly in intestinal epithelial cells (TECs) via IDO (~95 % of Trp); the gut microbiota pathway of direct transformation of Trp into indole metabolites (~5 % of Trp); and the serotonin or 5-hydroxytryptamine (5-HT) pathway in enterochromaffin cells (EC) via Trp hydroxylase 1 (TpHl) (~l-2 % of Trp). This represents the majority of body 5-HT production (~90 % of 5-HT). We have previously shown a critical role for the Trp-degrading enzyme, indoleamine 2, 3- dioxygenase 1 (IDO) in the fine-tuning of intestinal Trp metabolism under the obesogenic high- fat diet (HFD), with major consequences on metabolic syndrome (Laurans et al. 2018). However, the specific role of intestinal IDO in cardiometabolic diseases, including atherosclerosis, is still unknown. Moreover, although recent studies highlighted the local effects of Trp-derived metabolites in intestinal homeostasis, their systemic impact on atherosclerosis is poorly known. SUMMARY OF THE INVENTION: The present invention is defined by the claims. In particular, the present invention relates to the use of tryptophan hydroxylase 1 (TpHl) inhibitors for the treatment of atherosclerosis. DETAILED DESCRIPTION OF THE INVENTION: The present invention relates to a method of treating atherosclerosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a tryptophan hydroxylase 1 (TpHl) inhibitor. As used herein, the term “patient” or “subject” refers to any mammals, such as a rodent, a feline, a canine, and a primate. Particularly, in the present invention, the patient is a human. In some embodiments, the patient is a human who is susceptible to have atherosclerosis as described above. As used herein, the term “atherosclerosis” refers to the pathologic processes that leads to abnormal accumulation of cholesterol and cholesteryl esters and related lipids in macrophages, smooth muscle cell and other types of cells leading to narrowing and/or occlusion of one or several arteries and arterioles of the body and bodily organs, including but not limited to, the coronary arteries, aorta, renal arteries, corotid arteries, and arteries supplying blood to the limbs and central nervous system. The associated inflammatory reactions and mediators of this pathologic process also are included in this definition. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.