Habib, N

Habib, R

Huang, K-W

Huber, H

Jayaprakash, A

Muragundla, A

Reebye, V

Rossi, J

Saetrom, P

Vadnal, P

Voutila, J

Hepatology

English

Spiral - Imperial College Digital Repository

CONTROL ID: 2324221PRESENTATION TYPE: Oral or PosterCURRENT CATEGORY: Liver Fibrogenesis and Non-Parenchymal Cell BiologyCURRENT DESCRIPTORS: KO3. Clinical and Translational Fibrosis ResearchTITLE: Systemic administration of a novel development candidate, MTL-CEBPA, up-regulates the liver-enrichedtranscription factor C/EBP-α and reverses CCl4-induced liver failure in vivo.AUTHORS (FIRST NAME, LAST NAME): Vikash Reebye1, Jon Voutila2, Kai-Wen Huang3, 4, AnjaneyuluMuragundla5, Aravindakshan Jayaprakash5, Prashant Vadnal5, Hans Huber6, Robert Habib2, Pål Sætrom7, 8, JohnRossi9, Nagy Habib1Institutional Author(s): MiNA Therapeutics Ltd, London, United KingdomINSTITUTIONS (ALL): 1. DEPARTMENT OF SURGERY, IMPERIAL COLLEGE LONDON, London, United Kingdom.2. MiNA Therapeutics, London, United Kingdom.3. Department of Surgery and Hepatitis Research Centre, National Taiwan University Hospital, Taipei, Taiwan.4. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University Hospital, Taipei, Taiwan.5. Syngene, Bangalore, India.6. BioTD, Lansdale, PA, United States.7. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology,Trondheim, Norway.8. Department of Computer and Information Science, Norwegian University of Science and Technology, Trondheim,Norway.9. Molecular and Cellular Biology, City of Hope, Duarte, CA, United States.ABSTRACT BODY: Abstract Body: The transcription factor CCATT/enhancer binding protein alpha (C/EBP-α) is known to have animportant regulatory role in the maintenance of normal hepatocyte function and response to injury. We developed asmall activating RNA (saRNA) that was demonstrated to significantly up-regulate C/EBP-α expression in primaryhepatocytes. This saRNA was subsequently encapsulated in an anionic liposome as a development candidate forclinical use (MTL-CEBPA). Liver failure was induced in Sprague Dawley rats by twice weekly i.p. injection of CCl4 fora duration of 8 weeks. For a further 2 weeks of the CCl4 regiment, animals were treated by twice weekly i.v. injectionof MTL-CEBPA via tail vein at 0.3mg/kg, 1mg/kg and 3mg/kg. We demonstrate reversal and near normalisation of clinically relevant parameters following all treatment doses ofMTL-CEBPA including, at 3mg/kg, bilirubin (64% decrease), circulating alanine and aspartate aminotransferase (59%and 62% decrease respectively) and prothrombin time (19% decrease). We also observed a significant increase inserum albumin and total protein as well as a significant decrease in alkaline phosphatase and gamma-glutamyl-transpeptidase. Liver hydroxyproline significantly decreased in a dose-dependent manner in addition to a significantincrease in body weight with no associated toxicity. Here we present a novel development candidate, MTL-CEBPA, that safely up-regulates C/EBP-α, as a potentialtreatment for liver failure in vivo. Clinical studies with MTL-CEBPA are expected to begin in early 2016.(no table selected)(No Image Selected)Co-Author Disclosure Status  The following authors have completed their AASLD 2015 disclosure:: Vikash Reebye: Disclosure completed | JonVoutila: Disclosure completed | Kai-Wen Huang: Disclosure completed | Anjaneyulu Muragundla: Disclosurecompleted | Aravindakshan Jayaprakash: Disclosure completed | Prashant Vadnal: Disclosure completed | HansHuber: Disclosure completed | Robert Habib: Disclosure completed | Pål Sætrom: Disclosure completed | John Rossi:No Answer. | Nagy Habib: Disclosure completed

Systemic administration of a novel development candidate, MTL-CEBPA, up-regulates the liver-enriched transcription factor C/EBP-α and reverses CCl4-induced liver failure in vivo

http://spiral.imperial.ac.uk/bitstream/10044/1/32934/2/Systemic%20administration%20of%20a%20novel%20development%20candidate%2c%20MTL-CEBPA%2c%20up-regulates%20the%20liver-enriched%20abstract.pdf

Systemic administration of a novel development candidate, MTL-CEBPA, up-regulates the liver-enriched transcription factor C/EBP-α and reverses CCl4-induced liver failure in vivo

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