Oral delivery of a functional algal-expressed TGF-β mimic halts colitis in a murine DSS model

Danielle J Smyth,Bijie Ren,Madeleine P.J White,Caitlin Mcmanus,Holly Webster,Vivien Shek,Caroline Evans,Jagroop Pandhal,Francis Fields,Rick M Maizels,Stephen Mayfield

doi:10.1016/j.jbiotec.2021.08.006

Abstract

Inflammatory bowel disease (IBD) is a set of immunological disorders which can generate chronic pain and fatigue associated with the inflammatory symptoms. The treatment of IBD remains a significant hurdle with current therapies being only partially effective or having significant side effects, suggesting that new therapies that elicit different modes of action and delivery strategies are required. TGM1 is a TGF-β mimic that was discovered from the intestinal helminth parasite Heligmosomoides polygyrus and is thought to be produced by the parasite to suppress the intestinal inflammation response to help evade host immunity, making it an ideal candidate to be developed as a novel anti-inflammatory bio-therapeutic. Here we utilized the expression system of the edible green algae Chlamydomonas reinhardtii in order to recombinantly produce active TGM1 in a form that could be ingested. C. reinhardtii robustly expressed TGM1, and the resultant recombinant protein is biologically active as measured by regulatory T cell induction. When delivered orally to mice, the algal expressed TGM1 is able to ameliorate weight loss, lymphadenopathy, and disease symptoms in a mouse model of DSS-induced colitis, demonstrating the potential of this biologic as a novel treatment of IBD.

Highlights

Inflammatory Bowel Disease (IBD) is a chronic immunological disorder of the gastrointestinal tract that affects millions of people in the world (de Souza and Fiocchi, 2016; Kaser et al, 2010)
Because retinoic acid (RA) is a known enhancer of Foxp3 induction, similar assays were conducted with and without RA, but we found no significant increase in its presence with the different TGM preparations (Supplementary Fig. 3B)
Immuno-modulatory parasites are increasingly recognized as treasure chests of novel, biologically active products with therapeutic potential, for inflammatory disorders which are increasingly prevalent in industrialized societies (Johnston et al, 2009; Kahl et al, 2018; Maizels et al, 2018)

Summary

Introduction

Inflammatory Bowel Disease (IBD) is a chronic immunological disorder of the gastrointestinal tract that affects millions of people in the world (de Souza and Fiocchi, 2016; Kaser et al, 2010). The two principal types of IBD are Crohn’s disease (CD) (Baumgart and Sandborn, 2012) and ulcerative colitis (UC) (Danese and Fiocchi, 2011). While diagnosis is well-developed, no curative treatments for these diseases are available, with surgical resection a last resort. The detailed mechanism of IBD development is unclear, it is well acknowledged that IBD is associated with a failure of immune regulatory mechanisms, resulting in chronic inflammation and production of pro-inflammatory cytokines, leading to tissue destruction and tumorigenesis (Burisch et al, 2019; Neurath et al, 2002)

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Results

Conclusion