mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion
Taylor, Henry (Imperial College London)
Yerlioglu, Dilay (Istanbul University)
Phen, Claudia (University of Texas Southwestern Medical Center)
Ballauff, Antje (Zentrum für Kinder- und Jugendmedizin Gastroenterology)
Nedelkopoulou, Natalia (Sheffield Children's Hospital (Sheffield, Regne Unit))
Spier, Isabel (University of Bon)
Loverdos, Inés (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Busoni, Veronica B. (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Heise, Jürgen (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Dale, Peter (Hospital Italiano de Buenos Aires (Argentina))
de Meij, Tim (Amsterdam UMC. University Medical Center)
Sweet, Kevin (Ohio State University Wexner Medical Center)
Cohen, Marta C. (Sheffield Children's Hospital (Sheffield, Regne Unit))
Fox, Victor L. (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Mas, Emmanuel (Université de Toulouse)
Aretz, Stefan (University of Bonn)
Eng, Charis (Genomic Medicine Institute)
Buderus, Stephan (Case Western Reserve University School of Medicine)
Thomson, Mike (Sheffield Children's Hospital NHS Foundation Trus)
Rojas, Isabel (University of Texas Southwestern Medical Center)
Uhlig, Holm H. (University of Oxford)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0. 27, 95% confidence interval = 0. 07-0. 954, P = 0. 042) and resulted in significant improvements in the serum albumin level (mean increase = 16. 3 g/l, P = 0. 0003) and hemoglobin (mean increase = 2. 68 g/dl, P = 0. 0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29. 8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Human Molecular Genetics, Vol. 30 (april 2021) , p. 1273-1282, ISSN 1460-2083

DOI: 10.1093/hmg/ddab094
PMID: 33822054

10 p, 1.2 MB

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