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Innovative therapies in cardiometabolic and nutrition-related disorders

 

ICAN’s mission is to accelerate the development of specific therapies by leveraging the scientific excellence of its heart and metabolism community with cutting-edge translational research, improved care, training, and effective communication.

Following are several recent therapeutic highlights from each of our research domains.

 

Dyslipidemia

Eric Bruckert

Professor of Endocrinology, Clinical Investigator

 

Two areas are currently under active therapeutic research at ICAN: the treatment of hypercholesterolemia with antiPCSK9 antibodies, and the treatment of severe hypertriglyceridemia with antisense anti-apoCIII. The antiPCSK9 antibodies are subcutaneous injectable treatments that decrease LDL cholesterol by approximatively 50%. Their development is primarily focused on three groups of patients: 1) inherited hypercholesterolemia—a high risk vascular disease 2) in hypercholesterolemic patients intolerant to statins and 3) in those patients at high- or very high-cardiovascular risk who cannot achieve LDL-c targets with available therapies. Treatments are well tolerated, but the cost limits access to only the most severe patients. Accessibility will depend on current large clinical trial outcomes with specific clinical endpoints. For patients with severe hypertriglyceridemia, the therapeutic need is immensely important, even more so considering that previous therapy attempts failed. Antisense anti-apoCIII decreases hypertriglyceridemia via an innovative mechanism, and is of particular hope for those with hyperchylomicronemia, a severe illness responsible for recurrent pancreatitis.

 

  • Nissen SE, […] Bruckert E, et al. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15):1580-90. PMID: 27039291
  • Hopkins PN, […] Bruckert E, et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet. 2015 Dec;8(6):823-31. PMID: 26374825
  • Moriarty PM, […] Bruckert E, et al. Efficacy and safety of alirocumab vs ezetimibe instatin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015 Nov-Dec;9(6):758-69. PMID: 26687696
  • Raal FJ, Honarpour N, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):341-50. PMID: 25282520
  • Raal FJ, Stein EA, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40. PMID: 25282519

 

Obesity

Karine Clément

Professor of Nutrition, Clinical Investigator

 

In the late 90s and early 2000s Karine Clément discovered novel mutations in genes encoding the leptin receptor, POMC and MC4R. These genes encode proteins that belong to the leptin/melancortin pathway, a key pathway involved in body weight regulation. Patients with these mutations have severe forms of obesity, hyperphagia and sometimes hormonal abnormalities. In 2016, she conducted a treatment trial study with German colleagues and a US company showing impressive weight loss in two POMC deficient patients. This paves the way towards new therapies in patients with abnormalities in this melacortin pathway.

 

  • Kühnen P, Clément K, et al. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016 Jul21;375(3):240-6. PubMed PMID: 27468060
  • Clément K, Dubern B, et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab. 2008 Dec;93(12):4955-62. PubMed PMID: 18765507
  • Vaisse C, Clement K, et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest. 2000 Jul;106(2):253-62. PubMed PMID: 10903341
  • Vaisse C, Clement K, et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998 Oct;20(2):113-4. PubMed PMID: 9771699
  • Clément K, Vaisse C, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998 Mar 26;392(6674):398-401. PubMed PMID: 9537324

 

Christine Poitou-Bernert

Professor of Nutrition, Coordinator of the French Reference Center
for Prader-Willi Syndrome in adults

 

Rare syndromic obesities are characterized by severe early-onset obesity, with associated intellectual disability, neurosensorial and/or endocrine abnormalities. Prader-Willi syndrome (PWS) is the most common of these rare syndromic obesities. PWS is caused by a lack of paternal-origin imprinted allele expression on chromosome 15 and can now be diagnosed during the first month of life. PWS is characterized by a complete lack of appetite in early infancy, with subsequent development of hyperphagia and obesity. In 2015 we trialed the innovative desacylated ghrelin PWS treatment in collaboration with Alizé Pharma, and have participated in several French PWS trials (ocytocin, topiramate). Our objective is to accelerate the development of new therapies for PWS and other syndromic obesities. Studying these rare diseases over the past 10 years has led to a better understanding of the pathophysiological mechanisms involved in fat mass development and obesity-related cardiometabolic complications, and could help improve common obesity management.

 

  • Huvenne H, Dubern B, Clément K, Poitou C. Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016. Obes Facts. 2016;9(3):158-73. PMID: 27241181
  • Coupaye M, […] Clément K, Poitou C. Effect of genotype and previous growth hormone treatment on adiposity in adults with Prader-Willi syndrome. J Clin Endocrinol Metab. 2016 Sep 23:jc20162163. PMID: 27662437
  • Chevreul K, […] Poitou C, Tauber M. Economic burden and health-related quality of life associated with Prader-Willi syndrome in France. J Intellect Disabil Res. 2016 Sep;60(9):879-90. PMID: 27174598
  • Lacroix D, Moutel S, […] Clément K, Poitou C. Metabolic and adipose tissue signatures in adults with Prader-Willi syndrome: a model of extreme adiposity. J Clin Endocrinol Metab. 2015 Mar;100(3):850-9. PMID: 25478934
  • Lloret-Linares C, […] Clément K, Poitou C. Comparison of body composition, basal metabolic rate and metabolic outcomes of adults with Prader Willi syndrome or lesional hypothalamic disease, with primary obesity. Int J Obes (Lond). 2013 Sep;37(9):1198-203. PMID: 23318724

 

Lipodystrophy

Corinne Vigouroux

Endocrinologist & Clinical Investigator, Professor in Cell Biology

 

Our group investigates insulin resistance and lipodystrophic syndromes, and aims to develop improved medical care for affected patients. We discovered or aided in the discovery of several genes implicated in these diseases (BSCL2/seipin, PLIN1/perilipin, CIDEC, CAV1/caveolin-1, and PIK3R1) and described genotype-phenotype correlations at both clinical and cellular levels. We coordinate the French compassionate program of recombinant leptin (metreleptin) therapy in lipodystrophy patients. We recently showed that one-year metreleptin therapy, in addition to its beneficial effects on insulin sensitivity, also improves insulin secretion and decreases PCSK9 levels in patients with diabetes due to monogenic lipodystrophies, and could contribute to metabolic improvements. Metreleptin appears as a valuable therapeutic option for lipodystrophies and should be approved at the European level for routine use in these patients.

 

  • Brown RJ, […] Vigouroux C, Wabitsch M, Williams R, Yorifuji T. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J Clin Endocrinol Metab. 2016 Oct 6:jc20162466. PMID: 27710244
  • Vatier C, […] Vigouroux C, Cariou B. One-year metreleptin therapy decreases PCSK9 serum levels in diabetic patients with monogenic lipodystrophy syndromes. Diabetes Metab. 2016 Sep 27. pii: S1262-3636(16)30479-7. PMID: 27692500
  • Vatier C, […] Vigouroux C. One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes. Diabetes Obes Metab. 2016 Jul;18(7):693-7. PMID: 26584826
  • Salle-Teyssières L, […] Vigouroux C. Maladaptative Autophagy Impairs Adipose Function in Congenital Generalized Lipodystrophy due to Cavin-1 Deficiency. J Clin Endocrinol Metab. 2016 Jul;101(7):2892-904. PMID: 27144934

 

Liver Diseases

Chantal Housset

Research Team Director, Hepatologist, Professor in Cell Biology

 

Variations in the ABCB4 gene, encoding an ATP-binding cassette transporter (ABCB4/MDR3) mediating phosphatidylcholine secretion in hepatocytes, are responsible for hepatobiliary diseases. We have identified the majority of ABCB4 variations causing biliary diseases via gene sequencing. Missense variations in conserved ATP-binding motifs of ABCB4 are homologous to ABCC7/CFTR gating variations, which can be corrected by ivacaftor, a clinically approved cystic fibrosis (CF) drug. Bio-structural modeling of ABCB4 and CFTR led us to predict and then demonstrate defective activity in ABCB4 variants, which were then able to be rescued by ivacaftor. These results pave the way for personalized therapy in ABCB4-related diseases.

 

  • Delaunay JL,* Bruneau A,* […] Housset C, Callebaut I, Aït-Slimane T. Functional defect of variants in the ATP-binding sites of ABCB4 and their rescue by the CFTR potentiator, ivacaftor (VX-770). Hepatology 2016, in press.
  • Venot Q, […] Housset C, Maurice M, Aït-Slimane T. A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression. PLoS One. 2016 Jan 20;11(1):e0146962. PMID: 26789121
  • Delaunay JL, […] Housset C, Jacquemin E, Maurice M. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 2015;63(5):1620-31. Comments in: Hepatology 2016;63(5):1421-3.
  • Falguières T, […] Housset C, Maurice M. ABCB4: Insights from pathobiology into therapy. Clin Res Hepatol Gastroenterol. 2014 Oct;38(5):557-63. Review. PMID: 24953525
  • Gautherot J, […] Housset C, Maurice M, Falguières T. Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology. 2014 Aug;60(2):610-21. PMID: 24723470
  • Poupon R, […] Housset C, Barbu V. Genotype-phenotype relationships in the low-phospholipid associated cholelithiasis syndrome. A study of 156 consecutive patients. Hepatology 2013;58(3):1105-10.
  • Gautherot J, […] Housset C, Maurice M, Ait-Slimane T. Effects of cellular, chemical, and pharmacological chaperones on the rescue of a trafficking-defective mutant of the ATP-binding cassette transporter proteins ABCB1/ABCB4. J Biol Chem 2012;287(7):5070-78.

 

Vlad Ratziu

Professor of Hepatology, Clinical Investigator

 

ICAN’s clinical research teams are leading several translational studies investigating how targeting different metabolic, inflammatory or fibrotic pathways can reverse liver damage in patients with lipotoxic hepatic disease, which is associated with insulin resistance and metabolic syndrome. Well-designed randomized clinical trials use a model of liver damage called nonalcoholic steatohepatitis, one of the most prevalent chronic liver diseases. Early-concept, proof-of-concept, exploratory trials, and later, stage phase 2b or phase 3 trials are being designed by ICAN clinician scientists and conducted in patients with cardiometabolic factors seen by the hospital clinical services. Tested molecular targets include non-selective FXR agonists, second generation non-steroidal FXR agonists, dual or pan-PPAR agonists, drugs interfering with the lipogenic pathway (SCD1 inhibitors, and in 2017 ACC1 inhibitors), anti-inflammatory molecules (dual CCR2 and CCR5 antagonists; VAP1 inhibitors), molecules inhibiting JNK-induced apoptotic and inflammatory pathways through ASK-1 inhibition. As detailed in the references below, many of these therapeutic developments have the strong potential to improve treatment paradigms for many liver disease patients. Trials: Elafibranor NCT02704403; Obeticholic acid NCT02548351; JN452 NCT02855164; Aramchol NCT02279524; Cenicriviroc NCT02217475.

 

 

  • Scott Friedman*, Vlad Ratziu* et al. A randomized, placebo-controlled trial of cenicriviroc for the treatment of fibrotic nonalcoholic steatohepatitis. Submitted
  • Ratziu V, Harrison SA, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.e5. PMID: 26874076
  • Friedman S, […] Ratziu V. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016 Mar;47:356-65. PMID: 26944023
  • Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. J Hepatol. 2015 Apr;62(1 Suppl):S65-75. Review. PMID: 25920092
  • Ratziu V. Starting the battle to control non-alcoholic steatohepatitis.  Lancet. 2015 Mar 14;385(9972):922-4. PMID: 25468161
  • Ratziu V, Bedossa P, et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2014 Oct;12(10):1724-30.e5. PMID: 24530600
  • Ratziu V. Targeting non-alcoholic fatty liver disease through 11-βHSD1 inhibition. Lancet Diabetes Endocrinol. 2014 May;2(5):354-6. PMID: 24795242
  • Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol. 2013 Nov;10(11):676-85. Review. PMID: 24126564

 

Heart Disease

Stéphane Hatem

Professor of Cardiology, Research Unit Director, Clinical Investigator

 

Atrial fibrillation (AF) is associated with a high risk of systemic thromboembolism due to blood stasis in poorly contractile atria and a hypercoagulable state, so a majority of AF patients take anticoagulant therapies. In an animal model studied by Stéphane Hatem’s group, DTIs, including dabigatran, prevent or even reverse atrial remodeling and AF susceptibility associated with heart failure. This PAR-1–mediated effect is independent of anticoagulation DTI properties. The ongoing COMMANDER HF trial investigates whether targeted reduction of thrombin generation may improve clinical outcomes of patients with heart failure and coronary artery diseases. Its results should affirm or invalidate the clinical translation prospects of these observations in a rat model of heart failure-associated atrial remodeling.

 

  • Jumeau C, […] Hatem SN. Direct Thrombin Inhibitors Prevent Left Atrial Remodeling Associated With Heart Failure in Rats. JACC Basic Transl Sci. 2016 Jul 13;1(5):328-339. PMID: 27642643
  • Hatem SN. Atrial Fibrillation and Obesity: Not Just a Coincidence. J Am Coll Cardiol. 2015 Jul 7;66(1):12-3. PMID: 26139052

 

Medical Interventions

Alain Combes

Professor of Intensive Care Medicine, ICU Department Head

 

The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) remains controversial, with conflicting data regarding its impact on survival compared with conventional ventilator management. Beyond its currently accepted indication as a salvage therapy in refractory ARDS, ECMO may improve the outcomes of less severe ARDS patients by facilitating and maximizing lung-protective ventilation. Prof. Alain Combes coordinates the ongoing international multicenter randomized trial (EOLIA) testing the efficacy of early veno-venous ECMO in patients with severe ARDS, compared to a control group with precisely regulated mechanical ventilation. Results from this trial may help to resolve such controversies.

 

  • Papazian L, Herridge M, Combes A. Focus on veno-venous ECMO in adults with severe ARDS. Intensive Care Med. 2016 Nov;42(11):1655-1657. PMID: 27272761
  • Combes A, Ranieri M. Rescue therapy for refractory ARDS should be offered early: yes. Intensive Care Med. 2015 May;41(5):923-5. PMID: 25792205
  • Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2769-78. PMID: 24814488
  • Schmidt M, […] Combes A. The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med. 2013 Oct;39(10):1704-13. PMID: 23907497

 

Towards the Future

David Trégouët

Research Director in Human Genomics and Epidemiolomics of Cardiovascular Diseases

 

Within the last 3 years, David Trégouët and his French colleagues have discovered rare mutations in EIF2AK4 and RASGRP2 genes which cause inherited pulmonary veno-occlusive disease and severe bleeding disorders, respectively. Sequencing these genes is now routinely performed in clinics to aid in diagnosis and genetic counseling. These discoveries have also opened novel therapeutic perspectives for treating patients affected by these diseases. Dr. Trégouët also identified TSPAN15 and SLC44A2 genes as new genetic players in venous thrombosis susceptibility. Clinical investigations are ongoing to identify subgroups of patients at a higher risk of disease development or recurrence by assessing genetic information at these two genetic loci.

 

  • Eyries M, […] Tregouët DA, Humbert M, Soubrier F. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014 Jan;46(1):65-9. Pubmed PMID: 24292273
  • Canault M, […] Tregouet DA. Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding. J Exp Med. 2014 Jun 30;211(7):1349-62. Pubmed PMID: 24958846
  • Germain M, […] Trégouët DA, Smith NL, Morange PE. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet. 2015 Apr 2;96(4):532-42. Pubmed PMID: 25772935