Aleixo Muise, MD, PhD, FRCPC
The Hospital for Sick Children
Gastroenterology, Hepatology and Nutrition
Inflammatory Bowel Disease Centre
University of Toronto
Associate Professor, Biochemistry IMS
For more information, visit: Featured in: May Issue (Vol 28 Issue 5) of The Scientist Magazine: The Youngest Victims: Linking single-gene defects to inflammatory bowel disease in young children may help all sufferers of the illness.
Featured in: May Issue (Vol 28 Issue 5) of The Scientist Magazine: The Youngest Victims: Linking single-gene defects to inflammatory bowel disease in young children may help all sufferers of the illness.
Dr. Aleixo Muise received his B.Sc. from St. Francis Xavier University and then went on to complete a PhD in Biochemistry at Dalhousie University. Muise completed his MD at the University of Toronto and his Paediatric residency at SickKids and a Subspecialty Fellowship in the Division of Gastroenterology, Hepatology and Nutrition. He also completed Postdoctoral training in the laboratory of Dr. Daniela Rotin.
Inflammatory Bowel Disease
Muise is a Clinician-Scientist in the Cell Biology Program and Co-Director of the Inflammatory Bowel Disease (IBD) Centre. His clinical and research focus centers solely on understanding the pathogenesis of severe forms of intestinal disease in very young children, including inflammatory bowel disease (IBD). Unfortunately, these patients often do not respond to conventional therapies, suffer significant morbidity and are at risk of premature death. Our goal is to revolutionize the treatment of these young children by defining the underlying genetic causes so as to ultimately develop a precision medicine approach to therapy of their severe intestinal and inflammatory diseases.
To achieve this goal, I have established the first clinic focused exclusively on very young children at SickKids and established the National Early Onset Paediatric IBD Cohort Study (NEOPICS; www.NEOPICS.org). Collaborating international centers send my lab biological samples from children with intestinal and inflammatory disorders for genetic evaluation. This has led to large-scale funding and industry partnerships that have made my lab at SickKids an international leader in the study of paediatric gastrointestinal disease. Over the past 18 months we have identified the genetic cause for five novel diseases and used state-of-art techniques including animal models (mouse and zebrafish) and human intestinal organoids (mini-guts) to define the molecular defect. Some of these novel diseases have a primary intestinal defect (TTC7A and NHE3) while others have defects in capillaries (PLVAP), the immune system (TRIM22 and TTC7A), platelets and autoimmunity, and are often multi-systemic. Most importantly our studies have led to SickKids and international patients achieving cures from diseases that hitherto have been lifelong and life shortening.
Principal Investigator: Canadian National Early Onset Pediatric IBD Cohort Study (NEOPICS) http://www.neopics.org/
Canadian Institute of Health Research - Operating Grant: Genetic and Functional Studies in Very Early Onset-OBD (NEOPICS)
The Leona M. and Harry B. Helmsley Charitable Trust, Defining and Developing the Therapeutic Pipeline for VEO IBD: Toronto Studies
Crohn’s and Colitis Foundation of America and PROKIIDS: NEOPICS – Defining Very Early Onset IBD.
Crohn’s and Colitis Canada
2015 AGA/GRG - Young Investigator Award in Basic Science, Gastroenterology Research Group (GRG) and American Gastroenterology Association (AGA) http://paperity.org/p/73761133/grg-presidents-report
2010 George Ferry Young Investigator Development Award, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Society (NASPGHAN)
2014 Institute of Nutrition, Metabolism and Diabetes (INMD) New Investigator Partnership Prize
Canadian Institute of Health Research
2014 Canadian Association of Gastroenterology Young Investigator Award
Canadian Association of Gastroenterology
2011 Future Leaders in IBD (FLIBD) Award
2009-14 Early Researcher Award (ER08-05-087), Ontario Ministry of Research and Innovation
2008-12 New Investigator/Transition Award, Canadian Institute of Health Research (CIHR)/Crohn’s and Colitis Foundation of Canada (CCFC)/Canadian Association of Gastroenterology (CAG)
LOCAL (University of Toronto)
2012 Early Career Physician Researcher Award, Department of Paediatrics, University of Toronto
For a complete list of publications please see PubMed
Focused on VEOIBD and IBD
Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, Regueiro MD, Ngan BY, Xu W, Sherman PM, Silverberg MS, Rotin D. Protein-tyrosine phosphatase sigma is associated with ulcerative colitis. Current Biology 2007: 17(14): 1212-1218, PMID: 17614280
Muise AM, Walter TD, Glowacka WK, Griffiths AM, Ngan BY, Lan H, Xu W, Silverberg MS, Rotin D. Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn’s Disease. Gut 2009: 58(8):1121-1127, PMID: 19398441
Imielinski M, Baldassano R, Griffiths A, Russell R, Annese V, Dubinsky M, Kugathasan S, Bradfield J, Walters T, Sleiman P, Kim C, Glessner J, Saeed S, Muise AM, Grundmeier C, Castro M, Latiano PA, Dallapiccola B, Stempak J, Taylor K, Kirschner B, Stephens M, Levine A, Piccoli D, Denson L, Van Limbergen L, Cucchiara S, Guthery S, Wilson D, Grant S, Daly M, Silverberg M, Satsangi J, Hakonarson H. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nature Genetics 2009: 41(12):1335-1340, PMID: 19915574; PMCID: PMC3267927, Impact Factor: 35.5 [Provided functional data for this multi-centered GWAS]
Muise AM, Walters T, Xu W, Shen-Tu G, Guo CH, Fattouh R, Lam GY, Wolters VM, Bennitz J, Van Limbergen J, Renbaum P, Kasirer Y, Ngan BY, Turner D, Denson LA, Sherman PM, Duerr RH, Cho J, Lees CW, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Glogauer M, Silverberg MS, Brumell JH. Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 2011: 141(2): 633–641, PMID: 21684284: MCID: PMC3152589, **This manuscript was featured in a Gastroenterology Editorial**
Moran CJ, Walters TD, Guo CH, Kugathasan S, Klein C, Turner D, Wolters VM, Bandsma RH, Mouzaki M, Zachos M, Langer JC, Cutz E, Benseler SM, Roifman CM, Silverberg MS, Griffiths AM, Snapper SB*, Muise AM*. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflammatory Bowel Diseases 2013: 19(1):115-123, PMID: 22550014
Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R, Lam GY, Hu P, Murchie R, Sherlock M, Gana JC; NEOPICS, Russell RK, Glogauer M, Duerr RH, Cho JH, Lees CW, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Silverberg MS, Brumell JH. NADPH oxidase complex and IBD candidate gene studies: Identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 2012: 61(7): 1028-1035, PMID: 21900546; PMCID: PMC3806486
Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology 2012: 143(2): 285-288, PMID: 22727850
Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N, Muise AM, Shteyer E, Filiz S, Chee R, Elawad M, Hartmann B, Arkwright PD, Dvorak C, Klein C, Puck JM, Grimbacher B, Glocker EO. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. Journal of Allergy and Clinical Immunology 2013: 131(3): 825-830, PMID 23158016 [Analyzed 20 patients]
Lam GY, Cemma M, Muise AM, Higgins DE, Brumell JH. Host and bacterial factors that regulate LC3 recruitment to Listeria monocytogenes during the early stages of macrophage infection. Autophagy 2013: 9(7): 985-995, PMID: 23584039; PMCID: PMC3722333
Papapietro O, Teatero S, Thanabalasuriar A, Yuki KE, Diez E, Zhu L, Kang E, Dhillon S, Muise AM, Durocher Y, Marcinkiewicz MM, Malo D, Gruenheid S. R-spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea. Nature Communications 2013: 4:1898, PMID: 23695692
Theöni C, Amir A, Guo C, Zhang S, Avitzur Y, Heng YM, Cutz E, Muise AM. A novel nonsense mutation in the EpCAM gene in a patient with congenital tufting enteropathy. Journal of Pediatric Gastroenterology and Nutrition 2014 Jan: 58(1):18-21, PMID: 24048167
Dhillon S, Mastropaolo L, Griffiths C, Theöni C, Elkadri A, Xu W, Mack A, Walters T, Guo, Conghui, Mack D, Huynh H, Baksh S, Silverberg M, Brumell JH, Snapper SB, Muise, AM. Higher activity of the inducible nitric oxide synthase contributes to very early onset of inflammatory bowel disease. Clinical Translational Gastroenterology 2014 Jan 16: 5(1): e46. PMID: 24430113
Murchie R, Guo CH, Persaud A, Muise AM*, Rotin D*. Protein tyrosine phosphatase σ targets apical junction complex proteins in the intestine and regulates epithelial permeability. PNAS 2014 Jan 14: 111(2): 693-698. PMID: 24385580
Burghardt KM, Avinashi V, Kosar C, Xu W, Wales PW, Avitzur Y*, Muise AM*. A CARD9 polymorphism is associated with decreased likelihood of persistent conjugated hyperbilirubinemia in intestinal failure. PLoS One 2014: Jan 21; 9(1): e85915. PMID: 24465786
Shouval DS, Ouahed J, Biswas A, Goettel JA, Horwitz BH, Klein C, Muise AM, Snapper SB. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans. Advances in Immunology 2014: 122: 177-210. PMID: 24507158
Avitzur Y*, Guo C*, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, Elkadri A, Dhillon S, Murchie R, Fattouh R, Huynh H, Walker JL, Wales PW, Cutz E, Kakuta Y, Dudley J, Kammermeier J, Powrie F, Shah N, Walz C, Nathrath M, Kotlarz D, Puchaka J, Krieger J, Racek T, Kirchner T, Walters TD, Brumell JH, Griffiths AM, Rezaei N, Rashtian P, Najafi M, Monajemzadeh M, Pelsue S, McGovern DP, Uhlig HH, Schadt E, Klein C, Snapper SB, Muise AM. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 2014: 146(4): 1028-1039. PMID: 24417819. Impact Factor 16.7. **This manuscript was featured in “On the Cover” in Gastroenterology and in The Scientist Magazine**.
Murugan D, Albert MH, Langemeier J, Bohne J, Puchalka J, Järvinen PM, Hauck F, Klenk AK, Prell C, Schatz S, Diestelhorst J, Sciskala B, Kohistani N, Belohradsky BH, Müller S, Kirchner T, Walter MR, Bufler P, Muise AM, Snapper SB, Koletzko S, Klein C, Kotlarz D. Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. Journal of Clinical Immunology. 2014: Apr; 34(3): 331-339. PMID: 24519095
Czuczman MA, Fattouh R, van Rijn JM, Canadien V, Osborne S, Muise AM, Kuchroo VK, Higgins DE, Brumell JH. Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread. Nature 2014 May 8; 509(7499): 230-234. PMID: 24739967
Shouval DS, Biswas A, Goettel JA, McCann K, Conaway E, Redhu NS, Mascanfroni ID, Al Adham Z, Lavoie S, Ibourk M, Nguyen DD, Samsom JN, Escher JC, Somech R, Weiss B, Beier R, Conklin LS, Ebens CL, Santos FG, Ferreira AR, Sherlock M, Bhan AK, Müller W, Mora JR, Quintana FJ, Klein C, Muise AM, Horwitz BH, Snapper SB. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 2014 May 15: 40(5): 706-719. PMID: 24792912
Vy H.D. Kim, Rae Brager, Julia Upton, Bo Ngan, Andrea Newell, Maian Roifman, Aleixo M. Muise, Susanne M. Benseler, Eyal Grunebaum, Chaim M. Roifman. Hematopoietic stem cell transplantation completely reversed colitis but not arthritis in IL-10Rα deficiency. LymphoSign Journal, 2014, 1(2): 77-86
Lee CH, Hsu P, Nanan B, Nanan R, Wong M, Gaskin KJ, Leong RW, Murchie R, Muise AM*, Stormon MO*. Novel de novo mutations of the Interleukin-10 receptor gene lead to infantile onset inflammatory bowel disease. Journal of Crohn’s & Colitis. 2014 Nov 1;8(11):1551-6. PMID: 24813381
Dhillon SS, Fattouh R, Elkadri A, Xu W, Murchie R, Walters T, Guo CH, Mack D, Huynh H, Baksh S, Silverberg M, Griffiths AM, Snapper S, Brumell JH, Muise AM. Variants in NADPH oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology. 2014: 147(3): 680-89. PMID: 24931457 **This manuscript was featured in “Issue Highlights” in Gastroenterology**.
Benchimol EI, Mack DR, Nguyen GC, Snapper SB, Li W, Mojaverian N, Quach P, Muise AM. Incidence, Outcomes, and Health Services Burden of Very Early Onset Inflammatory Bowel Disease. Gastroenterology 2014:147(4): 803-13. PMID: 24951840. Impact Factor 16.7. **This manuscript was featured in “American Gastroenterology Association Editors Top Choice” and “CME Exam” in Gastroenterology **.
Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson D, Travis S, Turner D, Klein, Snapper S, Muise AM. Very early onset inflammatory bowel disease diagnostic approach to complex monogenic diseases. Gastroenterology 2014: 147(4): 990-1007. PMID: 25058236. Impact Factor 16.7. **This manuscript was featured in “On the Cover” in Gastroenterology**.
Shouval DR, Ebens CL, Murchie R, McCann K, Rabah R, Muise AM, Snapper SB. Large B-cell lymphoma in an adolescent patient with IL-10 receptor deficiency and history of infantile inflammatory bowel disease. In Press JPGN. PMID: 25141231
Moran CJ, Muise AM, Klein C, Snapper SB. Very Early Onset Inflammatory Bowel Disease – Gaining Insight through Focused Discovery. Inflammatory Bowel Disease Journal 2015: 21(5): 1166-75. PMID: 25895007
Gassas A, Courtney S, Armstrong C, Kapllani E, Muise AM, Schechter. Unrelated donor hematopoietic stem cell transplantation for infantile enteropathy due to IL-10/IL-10 receptor defect. Pediatr Transplant. 2015 Jun;19(4):E101-3. PMID: 25761563
Goettel JA, Biswas S, Lexmond WS, Yeste A, Passerini L, Patel B, Yang S, Sun J, Ouahed J, Shouval DS, McCann KJ, Horwitz BH, Mathis D, Milford EL, Notarangelo LD, Roncarolo MG, Fiebiger E, Marasco WA, Bacchetta R, Quintana FJ, Pai SY, Muise AM, Snapper SB. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood. Jun 18;125(25):3886-95. PMID: 25833964
*Elkadri A, *Thoeni C, *Deharvengt SJ, Murchie R, Guo CH, Stavropoulos JD, Marshall CR, Wales P, Cutz E, Roifman CM, Chitayat D, *Avitzur Y, *Stan RS, *Muise AM. Mutations in Plasmalemma Vesicle Associated Protein (PLVAP) Result in Sieving Protein Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia. Cellular and Molecular Gastroenterology and Hepatology. 2015 1(4): 381-393. **This manuscript was featured on the Cover, Editor's Essential Reading, an Editorial, and an AGA Press Release**
*Hayes P, *Dhillon S, *O’Neill K, Thoeni C, Hui KY, Elkadri A, Guo CH, Kovacic L, Aviello G, Alvarez LA, Griffiths AM, Snapper SB, Brant SR, Doroshow JH, Silverberg MS, Peter I, McGovern DPB, Cho J, Brumell JH, Uhlig HH, *Bourke B, *Muise AM, *Knaus UG. Defects in NADPH Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease. Cellular and Molecular Gastroenterology and Hepatology. 2015 1(5): 489-502. **This manuscript was featured on the Cover, an Editorial and in AGA edigest “Leading the news” http://www.gastro.org/journals-and-publications/aga-edigest-october-8-2015#1**
Janecke AR, Heinz-Erian P, Yin J, Petersen B-S, Franke A, Lechner S, Fuchs I, Melancon S, Uhlig HH, Travis S, Marinier E, Perisic V, Ristic N, Gerner P, Booth IW, Wedenoja S, Baumgartner N, Vodopiutz J, Frechette-Duval MC, De Lafollie J, Persad R, Warner N, Tse CM, Sud K, Zachos NC, Sarker R, Zhu X, Muise AM, Zimmer KP, Witt H, Zoller H, Donowitz M, and Müller T. Reduced sodium-proton exchanger NHE3 activity causes congenital sodium diarrhea. Human Molecular Genetics. September, 2015 1;24(23):6614-23. (We independently identified and characterized patient-9 and decided to join this multi-centered publication describing genetics of congenital sodium diarrhea).
Schwerd T, Pandey S, Yang HT, Bagola K, Jameson E, Jung J, Lachmann RH, Shah N, Patel SY, Booth C, Runz H, Düker G, Bettels R, Rohrbach M, Kugathasan S, Chapel H, Keshav S, Elkadri A, Platt N, Muise AM, Koletzko S, Xavier RJ, Marquardt T, Powrie F, Wraith JE, Gyrd-Hansen M, Platt FM, Uhlig HH. Impaired anti-bacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn’s disease. Accepted in Gut.
Thoeni C, Hamilton E, Elkadri A, Murchie R, Fiedler K, Ovadia A, Sharfe N, Ngan BY, Cutz E, Nahum A, Muise A*, Roifman CM*. The effects of STAT1 dysfunction on the gut. Accepted in LymphoSign Journal, 2015
Li Q*, Lee C*, Peters L*, Mastropaolo L, Thöni C, Elkadri A, Schwerd T, Zhu J, Zhang B, Zhao YZ, Hao K, Dinarzo A, Hoffman G, Kidd BA, Murchie, R, Al Adham Z, Guo C, Kotlarz D, Cutz E, Walters T, Shouval D, Curran M, Dobrin R, Brodmerkel C, Snapper S, Klein C, Brumell JH, Hu MJ, Nanan R, Snanter-Nanan B, Wong M, Le Deist F, Haddad E, Roifman CM, Gaskin K, Deslandres C, Griffiths AM, Uhlig H, Schadt E*, Muise AM*. Variants in TRIM22 that Affect NOD2 Signaling Are Associated With Very Early Onset Inflammatory Bowel Disease. Accepted in Gastroenterology.
Portrait by G.Baylon