Submucosal injection of the RNA nucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial.
Atreya R, Kuhbacher T, Waldner M, et al.
J Crohns Colitis 2023. doi: 10.1093/ecco-jcc/jjad162. Online ahead of print.
Despite an increasing number of therapeutic options for Ulcerative Colitis (UC), many patients still have disease which progresses over time, and there has been renewed interest in and improved understanding of the chronic fibrosis and remodelling that occurs in UC [1–3]. In particular, there has been a growing appreciation of both the importance of the extracellular matrix (ECM) for remodelling in UC and the potential to target the ECM with new therapeutic agents [4]. One such target is carbohydrate sulphotransferase 15 (CHST15). This is a type II transmembrane Golgi protein that biosynthesises highly sulphated disaccharide units (E-units) of chondroitin sulphate, which binds to various functional proteins and pathogenic microorganisms. Targeting this molecule in mouse models has previously been shown to offer promising signals for ameliorating colitis [5]. Based on this promising pre-clinical data, blockade of CHST15 has emerged as a potentially promising therapeutic target, and such blockade can be achieved by a silencing RNA oligonucleotide molecule called GUT-1 (previously called STNM01). A prior phase I clinical trial demonstrated the safety of GUT-1 in patients with Crohn’s Disease [6]. Accordingly, Atreya and colleagues now sought to evaluate the safety, as well as the efficacy and mode of action, of GUT-1 in patients with UC as part of a phase IIa placebo-controlled, clinical trial.
Patients will often ask, “What causes Inflammatory Bowel Disease?” Frustratingly, we remain unable to answer this seemingly simple question, beyond the often-quoted paradigm that unknown environmental factors trigger inflammation in genetically susceptible individuals. Although our understanding of the immune response in IBD has reached phenomenally detailed levels of resolution, the nature and identity of the initial environmental triggers of IBD have continued to remain a mystery. The strong relationship between socioeconomic development and IBD incidence is tantalising evidence of a definable environmental toxin and various substances such as processed food additives have recently been highlighted as potential suspects [1]. However, searching for the causative agent is like looking for a needle in a haystack as the candidate list includes literally every small molecule in existence!
Higher intra-abdominal visceral adipose tissue mass is associated with lower rates of clinical and endoscopic remission in patients with inflammatory bowel diseases initiating biologic therapy: Results of the Constellation Study
Despite an expanding therapeutic arsenal, a considerable proportion of patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) fail to achieve or sustain therapeutic responses [1, 2]. Mechanisms contributing to this failure, particularly with respect to biologic therapy, are only partially understood [3]. Uncovering the mechanisms behind loss of response may help to enhance the efficacy of existing treatment options or to develop alternative options for the future.
Some investigations have noted an association between obesity, high intra-abdominal visceral adipose tissue (IA-VAT) mass and unfavourable outcomes in individuals with Inflammatory Bowel Disease (IBD). However, these observations have been constrained by their methodology and have to date focused only on patients having treatment with anti-tumour necrosis factor alpha (anti-TNF-α) agents [4–6], limiting their scope.
The Constellation Study by Yarur and colleagues aimed to investigate the relationship between IA-VAT in patients with IBD and the response to biologic drugs with multiple different mechanisms of action.
The SONIC trial yielded seminal findings showing that the combination of infliximab and azathioprine is more effective than either treatment alone for the maintenance of remission in patients with Crohn’s Disease (CD) [1]. In recent years, despite the availability of an increasing number of biologics and small molecules to treat CD, a ceiling of therapeutic efficacy has been reached [2]. Therefore, there has been a resurgence of interest in whether this therapeutic ceiling “effect” can be overcome with new treatment combinations. In the EXPLORER study, the efficacy and safety of triple combination therapy was assessed using two biologics with different modes of action in association with methotrexate for the treatment of CD.
