Dominick L Auci, PhD, Senior Researcher, Department of Research and Development, TherapyX, 108 Biomedical Research Building, 3435 Main Street, Buffalo, NY 14214, United States. dauci@therapyxinc.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Laura Hammer, Stacia Furtado, Edith Mathiowitz, Dominick L Auci
Laura Hammer, Stacia Furtado, Dominick L Auci, Department of Research and Development, TherapyX, Buffalo, NY 14214, United States
Stacia Furtado, Edith Mathiowitz, Department of Molecular Pharmacology, Brown University, Providence, RI 02912, United States
Author contributions: Auci DL and Hammer L designed and coordinated the studies, analyzed data and wrote the manuscript; Hammer L performed in life phases and serum and tissue analysis; Furtado S, and Mathiowitz E prepared drug products and reviewed the manuscript.
Supported byNational Institute of Allergy and Infectious Diseases of the National Institutes of Health under award, No. 5R44AI080009.
Institutional animal care and use committee statement: All experiments were conducted in accordance with policies of the NIH Guide for the Care and Use of Laboratory Animals and Institutional Animal Care and Use Committee (IACUC) of the State University of New York at Buffalo, or Comparative Biosciences. Approved protocol MIC24125Y.
Conflict-of-interest statement: Dr. Auci reports grants from NIH, during the conduct of the study; In addition, Dr. Auci has a patent Micronized freeze-dried particles issued, and a patent Compositions for stabilizing and delivering proteins pending and Authors hold equity in Therapyx.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Dominick L Auci, PhD, Senior Researcher, Department of Research and Development, TherapyX, 108 Biomedical Research Building, 3435 Main Street, Buffalo, NY 14214, United States. dauci@therapyxinc.com
Received: May 7, 2020 Peer-review started: May 7, 2020 First decision: June 7, 2020 Revised: June 18, 2020 Accepted: October 9, 2020 Article in press: October 9, 2020 Published online: November 8, 2020 Processing time: 182 Days and 12.2 Hours
Abstract
BACKGROUND
TreXTAM® is a combination of the key regulatory cytokine transforming growth factor beta (TGFβ) and all trans retinoic acid (ATRA) microencapsulated for oral delivery to immune structures of the gut. It is in development as a novel treatment for inflammatory bowel disease (IBD).
AIM
To measure TGFβ levels in blood and tissue after oral administration of encapsulated TGFβ.
METHODS
Animals were orally administered encapsulated TGFβ by gavage. Levels of drug substance in blood and in gut tissues at various times after administration were measured by ELISA.
RESULTS
We made the surprising discovery that oral administration of TreXTAM dramatically (approximately 50%) and significantly (P = 0.025) reduced TGFβ levels in colon, but not small intestine or mesenteric lymph nodes. Similarly, levels in rat serum after 25 d of thrice weekly dosing with either TreXTAM, or microencapsulated TGFβ alone (denoted as TPX6001) were significantly (P < 0.01) reduced from baseline levels. When tested in the SCID mouse CD4+CD25- adoptive cell transfer (ACT) model of IBD, oral TPX6001 alone provided only a transient benefit in terms of reduced weight loss.
CONCLUSION
These observations suggest a negative feedback mechanism in the gut whereby local delivery of TGFβ results in reduced local and systemic levels of the active form of TGFβ. Our findings suggest potential clinical implications for use of encapsulated TGFβ, perhaps in the context of IBD and/or other instances of fibrosis and/or pathological TGFβ signaling.
Core Tip: The observations suggest a negative feedback mechanism in the gut whereby local delivery of transforming growth factor beta (TGFβ) to immune structures of the gut results in reduced local and systemic levels of the active form of TGFβ.
