Current and emerging therapies for coeliac disease

Kivelä, Laura; Caminero, Alberto; Leffler, Daniel A.; Sánchez, María Inés Pinto; Tye–Din, Jason A.; Lindfors, Katri

doi:10.1038/s41575-020-00378-1

Cited by 80 publications

(83 citation statements)

References 121 publications

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“…These therapies may target patients who are on a GFD but have ongoing symptoms and/or intestinal damage due to inadvertent gluten exposure. Currently, a diverse range of mechanisms is being investigated ( 11 ), and it is possible that selected therapeutics could be used for a broader segment of the patient population.…”

Section: Introductionmentioning

confidence: 99%

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

et al. 2021

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Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.

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Section: Introductionmentioning

confidence: 99%

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

et al. 2021

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“…As yet, none of the drugs designed to sequester undigested gluten peptides within the intestinal lumen, 7 to enhance their intraluminal digestion 8 or to supposedly block their epithelial passage, 9,10 have proven to be sufficient efficacious. 6 Pulz et al 1 now report results with a novel computationally designed synthetic glutenase (Kuma-30, TAK-062). They first demonstrated its efficacy to degrade gluten in vitro, in a dynamic gastric model and its good tolerability in 14 healthy volunteers and 9 patients with CeD.…”

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confidence: 98%

“…Several therapies have recently been developed based on our advanced understanding of disease pathogenesis (Figure 1), which defines CeD as a T-helper-1 cell-driven autoimmune-like enteropathy induced by dietary gluten in individuals carrying the human lymphocyte antigens (HLA) DQ2 and/or DQ8. [4][5][6] A first set of therapeutic strategies aims at reducing the amount of immunogenic gluten peptides that can reach the lamina propria and stimulate the immune system. As yet, none of the drugs designed to sequester undigested gluten peptides within the intestinal lumen, 7 to enhance their intraluminal digestion 8 or to supposedly block their epithelial passage, 9,10 have proven to be sufficient efficacious.…”

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confidence: 99%

“…4,5 Cytokines produced by gluten-activated CD4þ T cells (interferon [IFN] g, interleukin [IL] 2, IL21) and stressed myeloid and epithelial cells (IL15) orchestrate further T-cell expansion and activation of cytotoxic CD8þ intraepithelial lymphocytes (IELs), leading to villous atrophy. 12,13 Based on these insights (Figure 1), 3 therapeutic approaches are being explored: TG2 blockers to prevent deamidation of gluten peptides and their efficient presentation to CD4þ T cells 6,13 ; anti-IL15 antibodies to inhibit epithelial damage 14 or oppose the outgrowth of malignant IELs in type II refractory CeD 15 ; and immunotherapy to restore tolerance to gluten. The latter strategy is explored by Kelly et al in this issue of Gastroenterology.…”

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confidence: 99%

“…17,18 However, this approach was suspended as protection against villous atrophy and digestive symptoms upon subsequent oral gluten challenge was not reached. 6 Kelly et al tested a different immunotherapy that used intravenous infusions of negatively charged biodegradable 500 nm poly-D,L-lactide-co-glycolide nanoparticles loaded with a mixture of native and deamidated gliadin peptides (TAK-101). 2 Prior mouse models of autoimmunity and delayed hypersensitivity demonstrated that such nanoparticles loaded with the respective autoantigens or allergens mainly addressed antigen-presenting cells in the spleen, reducing activation or inducing anergy in specific effector CD4þ and CD8þ T cells, while stimulating expansion of antigen-specific regulatory T cells (Tregs).…”

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The Promise of Novel Therapies to Abolish Gluten Immunogenicity in Celiac Disease

Cerf‐Bensussan

Schuppan

2021

Gastroenterology

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Evolution in coeliac disease diagnosis and management

Tye‐Din

2024

JGH Open

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The traditional gut‐centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease ‐ well demonstrated in children ‐ are growing for adults. Novel biomarkers such as interleukin‐2 that identify the gluten‐specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case‐finding strategy and enthusiasm for population screening is growing. The gluten‐free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly‐responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super‐sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.

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Current and emerging therapies for coeliac disease

Cited by 80 publications

References 121 publications

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development

The Promise of Novel Therapies to Abolish Gluten Immunogenicity in Celiac Disease

Evolution in coeliac disease diagnosis and management

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