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EP-4735019-A1 - METHODS OF TREATMENT OF METABOLIC DISORDERS

EP4735019A1EP 4735019 A1EP4735019 A1EP 4735019A1EP-4735019-A1

Abstract

METHODS OF TREATMENT OF METABOLIC DISORDERS In the present invention SLC5A9 gene (encoding SGLT4 protein) regulation was analyzed in the intestine of patients before and after weight-loss surgery. RNA scope analysis was used to determine the precise location of SLC5A9 in the human intestine and pancreas. Sglt4 knock- out (KO) mice were created using CRISPR/Cas techniques, allowing to study changes in their metabolic phenotype for months while they were fed the WD (Western Diet). So, these data demonstrate that SLC5A9 mRNA levels are induced in the apical membrane of the intestine and exocrine pancreas in persons with obesity and Type 2 Diabetes. Furthermore, Sglt4 deficiency slows the onset of obesity and hyperglycemia in mice fed the WD, improving insulin sensitivity by improving beta cell function. Accordingly the present invention relates to a method for preventing or treating metabolic disorders by targeting the Sodium-Glucose-Co- Transporter-4 (SGTL4).

Inventors

  • BONNER, Caroline

Assignees

  • Institut National de la Santé et de la Recherche Médicale
  • Centre Hospitalier Universitaire de Lille
  • Université de Lille
  • Institut Pasteur de Lille

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1. A Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use in the treatment of a patient affected with a metabolic disorder.
  2. 2. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 1 wherein said inhibitor directly binds to Sodium-Glucose-Co-Transporter- 4 (SGTL4) (protein or nucleic sequence (DNA or mRNA)) and/or ii) inhibits serum concentrations of SGLT4 substrates (through blocking Sodium-Glucose- Co-Transporter-4 (SGLT4) transport sugar process) and/or iii) elevating glucose sensitivity/tolerance and/or insulin sensitivity.
  3. 3. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 1 to 2 wherein metabolic disorder is selected from the list consisting of overweight, obesity, hepatic steatosis or fatty liver, dyslipidemia and in particular, hypercholesterolemia and/or hypertriglyceridemia; hyperglycemia, insulin resistance and diabetes, preferably Type 2 diabetes and gestational diabetes; metabolic syndrome, chronic renal failure, hypertension and cardiovascular diseases.
  4. 4. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 3 wherein the metabolic disorder is selected from the list consisting of overweight, obesity, insulin resistance and diabetes, preferably Type 2 diabetes.
  5. 5. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 4 wherein the metabolic disorder is Type 2 diabetes.
  6. 6. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to any of claim 1 to 5 to prevent the progression of the metabolic disease to pancreatic cancer, liver cancer, colorectal cancer, kidney cancer, uterine cancer or breast cancer.
  7. 7. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to any one of claim 1 to 6 wherein said inhibitor is 1) an inhibitor of Sodium-Glucose-Co-Transporter-4 (SGTL4) activity and/or 2) an inhibitor of Sodium-Glucose-Co-Transporter-4 (SGTL4) gene expression.
  8. 8. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 7 wherein said inhibitor of Sodium-Glucose-Co-Transporter-4 (SGTL4) activity is selected from the list consisting of an anti-Sodium-Glucose-Co- Transporter-4 (SGTL4) neutralizing antibody, an anti-Sodium-Glucose-Co- Transporter-4 (SGTL4) aptamer.
  9. 9. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to claim 7 wherein the inhibitor of Sodium-Glucose-Co-Transporter-4 (SGTL4) gene expression is selected from the list consisting of antisense oligonucleotide, nuclease, siRNA, shRNA or ribozyme nucleic acid sequence.
  10. 10. The Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use according to any one of claim 1 to 9, in a subject having a higher level of SGTL4 in a biological sample as compared to a predetermined reference value.
  11. 11. A method of preventing or treating metabolic disorder in a subject comprising administering to the subject a therapeutically effective amount of a Sodium- Glucose-Co-Transporter-4 (SGTL4) inhibitor and an Sodium-Glucose-Co- Transporter-2 (SGTL2) inhibitor.
  12. 12. The method of preventing or treating metabolic disorder according to claim 11 wherein said Sodium-Glucose-Co-Transporter-2 (SGTL2) inhibitor is (A) Inhibitor of Sodium-Glucose-Co-Transporter-2 (SGTL2) activity such as small organic molecule or anti- SGTL2 antibody (neutralizing antibody) B) Inhibitor of Sodium-Glucose-Co-Transporter-2 (SGTL2) gene expression selected from the list consisting of antisense oligonucleotide, nuclease, siRNA, shRNA or ribozyme nucleic acid sequence.
  13. 13. The method of preventing or treating according to claim 11 and 12 wherein the metabolic disorder is selected from the list consisting of overweight, obesity, hepatic steatosis or fatty liver, dyslipidemia and in particular, hypercholesterolemia and/or hypertriglyceridemia; hyperglycemia, insulin resistance and diabetes, preferably Type 2 diabetes mellitus and gestational diabetes; metabolic syndrome, chronic renal failure, hypertension and cardiovascular diseases
  14. 14. The method of preventing or treating according to claim 13 wherein the metabolic disorder is selected from the list consisting of overweight, obesity, insulin resistance and diabetes, preferably Type 2 diabetes mellitus.
  15. 15. A method for screening a Sodium-Glucose-Co-Transporter-4 (SGTL4) inhibitor for use in the treatment or prevention of metabolic disorder which comprises the step consisting of: (i) providing purified SGLT4 protein, providing a cell, tissue sample or organism expressing the SGLT4, (ii) providing a candidate compound such as small organic molecule, nucleic acids, antibodies, peptide or polypeptide, (iii) measuring the activity of the SGLT4, (iv) and selecting positively candidate compounds that, blocks the biological activity of SGLT4 or inhibits SGLT4 expression.

Description

METHODS OF TREATMENT OF METABOLIC DISORDERS FIELD OF THE INVENTION: The present invention relates to a method for preventing or treating metabolic disorders such as Type 2 Diabetes and obesity by targeting the Sodium-Glucose-Co-Transporter-4 (SGTL4). BACKGROUND OF THE INVENTION: A perennial challenge facing all of the world's countries, regardless of their level of economic development, is addressing the epidemic of obesity which has become a pandemic. According to the World Health Organization, more than 1.9 billion adults, 18 years and older, were overweight. Of these 650 million were obese h Worldwide obesity has almost tripled and the key ingredients contributing to this are a sedentary lifestyle, a high-fat, and high-sugar diet, known as the Western diet (WD), ubiquitous access to convenience foods, or spending less time preparing meals at home 2. Childhood obesity has doubled in children and quadrupled in adolescents since the 1980s 3. Collectively, these transitions have radically affected human metabolic health status worldwide. Obesity is characterized by excessive accumulation and storage of fat which is a leading risk factor for the development of non-alcoholic fatty liver disease (NAFLD), T2D, cardiovascular disease (CDV), and certain cancers, thus causing premature mortality and disability worldwide 4’5. Despite these facts, control of carbohydrate consumption, including that of dietary sugars, and their relevance in the global rise of obesity in adults, adolescents, and children remains controversial 6. This is not surprising since it was just in the recent past, that the ruminant consumption of trans-saturated fats was considered a major public health concern for their detrimental effects on metabolic disease 7. The majority of studies in the last three decades have focused on glucose transporters, such as SGLT1, SGLT2, and GLUT2, which seemed relevant at the time, since sucrose was universally referred to as 'table sugar’ and was a stable commodity in the diet. However, the composition of the WD is not only of sucrose, and fat, but also high-fructose-corn-syrup (HFCS), which is actively transported by SGLT4 and GLUT5 8. The Western-style dietary pattern is largely linked to the rise in obesity, which is characterized by the chronic overconsumption of foods enriched in refined sugars such as sucrose, HFCS, salt, proteins derived from fatty domesticated and processed meats, and trans-saturated fats, with time, exacerbate all chronic diseases of civilization. It potentiates 1) glycemic load, 2) fatty acid composition, 3) macronutrient composition, 4) micronutrient density, 5) acid-base balance, 6) sodium-potassium ratio, 7) fiber content, and 8) aging 9-11. Although the majority of metabolic studies of sugar metabolism have focused mostly on glucose because of its fundamental role in energy generation and metabolic diseases the blame has now been shifted to fructose-containing sugars 12. Nevertheless, all metabolic diseases share a common origin - a disruption in the balance of sugar metabolism and hormone secretion, commonly referred to as glucose homeostasis. Central to this balance are glucose transporters, some of which are subject to adaptation and inhibition. Some adaptations of glucose transporters may promote or worsen metabolic diseases and certain cancers 13, while their inhibition can favorably alter the pathophysiology of these diseases 14,15. Beyond these noticeable observations, our knowledge of the inter-organ crosstalk of sugar transporter adaptation and /or inhibition in metabolic disease is severely limited. For the first time in history, public health authorities are predicting that the younger generation will have a shorter life span than their parents 16. As can be imagined, this debilitating and chronic disease carries a substantial economic burden on individuals and society. Worldwide health authorities must now invest in research to develop sustainable therapeutic strategies to prevent obesity, and its correlates, Non Alcoholic Fatty Liver Disease (NAFLD), Type 2 Diabetes (T2D), and Cardiovascular diseases (CVD). Unlike some of its better-known family members, SGLT4 also exhibits a Na+-dependent alpha-methyl-D-glucopyranoside (AMG) transport system with a Km of 2.6 mM, suggesting that it is a low affinity-type transporter 17, similar to that of SGLT2 18. Early studies by Alton and colleagues suggested that approximately 95-98% of mannose entering the cell is transported by an ‘unknown sodium-dependent-mannose-transport-system where it is catabolized, while only 2% of mannose is used for N-glycosylation 19. Later studies using radiolabeled mannose suggested that an ‘SGLT4-like transport system ’ might be physiologically relevant for intestinal absorption and renal reabsorption 17’20,21. But, unlike SGLT1 and SGLT2, which transports only glucose 22 , SGLT4 transports naturally occurring sugars with a rank order of mannose, followed by glucose, fructose, 1,5-anhydro-D-glu