Challenges to drug discovery for celiac disease and approaches to overcome them

ABSTRACT

Introduction: The only available effective treatment for celiac disease (CD) is strict and long-term compliance with a gluten-free diet. Dietary gluten restriction must be strict and long term, but is difficult to achieve in many cases and alternative dietary strategies have been investigated in the past few years.

Areas covered: This review highlights the progress that has been made in the development of new therapeutics for CD. Detailed information is provided on the targets of drugs for CD as their related mechanisms of action. The therapies are classified in five mechanisms: modification of gluten, intraluminal therapies, immunomodulation, intestinal permeability and modulation of adaptative response. The actual development phase and future approach are also described and discussed.

Expert opinion: There are several limitations in each of the treatment targets related either through complications or the lack of complete response to a normal gluten containing diet. It is clear that the most desired therapy for celiac patients would induce gluten tolerance and progress has been made as per the treatments described herein. Therefore, it is shortly expected that curative or complimentary tools to a gluten free diet will be available that will improve the quality of life of CD sufferers.

KEYWORDS:

• Celiac disease
• gluten tolerance
• immunomodulation
• proteases
• tissue transglutaminase
• Intestinal permeability

Article highlights

• Celiac disease (CD) is caused by a dysregulated immune response towards dietary gluten in genetically susceptible individuals.

• The only effective treatment for CD is a life-long strict gluten-free diet (GFD).

• GFD compliance can be however difficult to achieve while some patients do not fully respond to it, making therefore the development of alternative therapies as a real need.

• Alternative therapies/approaches to GFD currently under development can be broadly divided into 4 categories including: i) gluten detoxification; ii) intraluminal therapies for gluten digestion/neutralization in the gastrointestinal tract; iii) modulation of the immune system; and iv) modulation of the intestinal permeability

• Although in most cases these alternative therapies will not be as cost-effective as the GFD, they would provide novel treatment for patients who are refractory to GFD, while they would also increase the quality of life of CD patients.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was funded in part by a grant from the Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, (Ref PI13/01133 and PI16/01574), co-funded by FEDER (European Regional Development Fund).