Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn’s Disease Patients with Active Mucosal Lesions

Suzuki, Kenji; Yokoyama, Junji; Kawauchi, Yusuke; Honda, Yutaka; Sato, Hiroki; Aoyagi, Yoshinobu; Terai, Shuji; Okazaki, Kazuichi; Suzuki, Yasuo; Sameshima, Yukinori; Fukushima, Tsuneo; Sugahara, Kazuyuki; Atreya, Raja; Neurath, Markus F.; Watanabe, Kenichi; Yoneyama, Hiroyuki; Asakura, Hitoshi

doi:10.1093/ecco-jcc/jjw143

Cited by 43 publications

(44 citation statements)

References 29 publications

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“…In chronic dextran sulfate sodium colitis, CHST15 Nature Reviews | Gastroenterology & Hepatology siRNA reduced colitis activity and numbers of α SMA (smooth muscle actin) positive fibroblasts and collagen deposition. Furthermore, a phase I study in 18 patients with Crohn's disease published in 2016 determined the safety of STNM01, a synthetic double stranded RNA oligonucleotide directed against CHST15, in Crohn's disease 79 . The majority of individuals who received STNM01 showed a reduction of endoscopic inflam mation as compared with placebo therapy.…”

Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

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507

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“…Interestingly, STNM01 possess rather protective effect to muscle layer. Indeed, there was no sign of perforation and fistula in phase 1 study and its long-term observation over 1 year (26). Thus, anatomy-based, appropriate anti-fibrosis therapy does not increase the risk of perforation or fistula because it does not impact on muscle layer.…”

Section: Mechanism Why Anti-fibrotic Drug Stnm01 Induces Mh In Refracmentioning

confidence: 86%

“…STNM01 is a synthesized double stranded RNA oligonucleotide that selectively inhibits the expression of CHST15 gene (25,26). STNM01 (or experimental grade of CHST15 siRNA with the same sequence; hereafter we refer both as "STNM01") suppressed CHST15 mRNA in human colon and lung fibroblast cell lines in vitro and reduced the expression of CHST15 mRNA in the colon of mouse DSS colitis (25), the esophagus of pig esophageal stricture post ESD (27), the lung of mouse pulmonary fibrosis (28) and the heart of rat myocarditis (29).…”

Section: Mode Of Action Of Chst15 Inhibitor Stnm01 In Fibrosismentioning

confidence: 99%

“…For CD, we took an approach to focal injection as most CD patients have localized ulcers and lesions (26). In accordance with "lifting-up" technique before endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) against localized gastrointestinal caners, STNM01 was submucosally administered to surround the periphery of the target, localized lesion ( Figure 3) in a phase 1 first-inpatient clinical trial (26).…”

Section: Clinical Application For Ibd and Evidence Of Target Chst15 Rmentioning

confidence: 99%

“…Phase 1 first-in-patient trial was conducted for patients with CD who do not respond to conventional treatment including biologics (hereafter, "non-healer") and endoscopy as well as histology were investigated as secondary endpoints (26). Figure 5 shows a typical patient depicting deep ulcer despite intensive treatment with infliximab for Figure 5A).…”

Section: Induction Of Quick Mh Response By Stnm01 With Antifibrotic Amentioning

confidence: 99%

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New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Suzuki

Yoneyama

2017

Ann. Transl. Med.

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Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue-specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target-and tissue-specific findings-based strategy would be a key to translation in developing anti-fibrosis therapy.

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Improvement of Cell Penetrating Peptide for Efficient siRNA Targeting of Tumor Xenografts in Zebrafish Embryos

Laroui

Cubedo

Rossel

2020

Advanced Therapeutics

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Cell‐penetrating peptides (CPPs) are one of the most efficient vectors for achieving cellular uptake of different cargos. However, their application in cancer therapy is greatly limited due to the lack of tissue selectivity, as they are widely distributed in most tissues following in vivo administration. To introduce specificity and improve tumor targeting, a combination of a cell‐penetrating peptide (CADY) and a targeting ligand, the laminin receptor binding peptide (YIGSR) to target the 37/67 kDa laminin receptor, known to be upregulated in most cancer cells and to be correlated with the invasiveness and metastatic potential, is formulated. The targeting CPP named “Y‐CADY” does not induce any change in the physico‐chemical properties (secondary structure, small interference RNA (siRNA) complexation, size, and charge) of CADY. Interestingly, Y‐CADY is more efficient than CADY for gene silencing in cell lines, and more potent for targeting and for inducing apoptosis of tumor xenografts in zebrafish embryos. The present study demonstrates that the novel targeting CPP “Y‐CADY” is efficient for gene silencing and can serve as a vector to target cancer cells in vivo.

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Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn’s Disease Patients with Active Mucosal Lesions

Abstract: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions.

Cited by 43 publications

References 29 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Improvement of Cell Penetrating Peptide for Efficient siRNA Targeting of Tumor Xenografts in Zebrafish Embryos

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