Published online Nov 8, 2020. doi: 10.4292/wjgpt.v11.i5.79
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
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).
When given together, ATRA and TGFβ signals synergize in promoting the differentiation and stabilization of regulatory T cells.
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.
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.
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.
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.
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.