Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. Nov 8, 2020; 11(5): 79-92
Published online Nov 8, 2020. doi: 10.4292/wjgpt.v11.i5.79
Oral encapsulated transforming growth factor β1 reduces endogenous levels: Effect on inflammatory bowel disease
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 by National 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.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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/
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
ARTICLE HIGHLIGHTS
Research background

TreXTAM® is a combination of 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).

Research motivation

When given together, ATRA and TGFβ signals synergize in promoting the differentiation and stabilization of regulatory T cells.

Research objectives

This is a completely novel strategy for the treatment of IBD, as no similar products currently exist. TreXTAM would represent an entirely novel IBD treatment modality.

Research methods

During TreXTAM development, we studied TGFβ pharmacokinetics after oral administration of TreXTAM, or after the encapsulated cytokine (TPX6001) was given alone, without ATRA. This is required for combinatorial products.

Research results

We made the surprising discovery that oral administration of TreXTAM dramatically reduced TGFβ levels in colon and in blood, to below baseline levels. When encapsulated TGFβ (TPX6001) was given alone, three times a week for 25 d, we likewise observed serum TGFβ decreases below baseline (untreated) levels. Oral treatment with TPX6001 alone transiently ameliorated weight loss in the murine adoptive cell transfer model of IBD, chosen because it recapitulates regulatory T cell immunology associated with disease.

Research conclusions

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. This finding suggests potential clinical implications for use of encapsulated TGFβ in the context of IBD and/or pathological TGFβ signaling.

Research perspectives

Additional studies in the ACT model, as well as other models of acute and chronic IBD, will be necessary to fairly evaluate the therapeutic potential of oral TreXTAM, as well as TPX6001 when given alone in IBD, autoimmune diseases, and perhaps also in other specific clinical situations where increasing TGFβ levels are pathogenic, for example against certain challenging forms of breast cancer. Such studies are subjects of forthcoming work from our laboratories.