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Celiac disease - Improving enzymatic oral therapies via polymer conjugation

Applicant Leroux Jean-Christophe
Number 135732
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Pharmacology, Pharmacy
Start/End 01.11.2011 - 31.03.2015
Approved amount 288'000.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Biomedical Engineering

Keywords (5)

Celiac disease; Drug delivery; Enzymes; Bioadhesion; Imaging

Lay Summary (English)

Lead
Lay summary

Celiac disease (CD) is an inflammatory disease of the intestine nutritional deficiencies, osteoporosis, secondary autoimmune disorders, malignancies). Hence, there is an urgent need for complementary non-dietary therapies to help treating this common disorder (~1% of the population). CD is induced by immunogenic sequences of gluten proteins which are highly resistant to human digestive proteases. One of the most interesting therapeutic options consists in administering to CD patients exogenous enzymes (“glutenases”) that cleave and detoxify the gluten peptides. While promising, this approach is in part limited by the relative e.g., triggered in genetically predisposed individuals by the ingestion of gluten and gluten-like proteins of wheat, rye, and barley. There is increased morbidity and mortality associated with CD. The current and only treatment is life-long elimination of gluten from the diet. This dietary restriction is a difficult experience for many patients and is often associated with a decreased quality of life. Poor compliance, whether inadvertent or voluntary, to a strict gluten-free diet is frequent and predisposes patients to CD complications (instability of the enzymes in the harsh conditions encountered in the GI tract. The objective of this research is increase the stability and efficacy of glutenases through polymer conjugation. In parallel, we will develop imaging tools to monitor in real time the glutenase activity in the GI tract. We believe CD patients would be better controlled if their daily diet could tolerate minimal amounts of gluten and therefore there is an urgent need for new therapeutic and/or adjuvant modalities.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Site-Specific Polymer Conjugation Stabilizes Therapeutic Enzymes in the Gastrointestinal Tract
Schulz Jessica D., Patt Melanie, Basler Sophie, Kries Hajo, Hilvert Donald, Gauthier Marc A., Leroux Jean-Christophe (2016), Site-Specific Polymer Conjugation Stabilizes Therapeutic Enzymes in the Gastrointestinal Tract, in ADVANCED MATERIALS, 28(7), 1455-1460.
Improving the Stability and Activity of Oral Therapeutic Enzymes-Recent Advances and Perspectives
Fuhrmann Gregor, Leroux Jean-Christophe (2014), Improving the Stability and Activity of Oral Therapeutic Enzymes-Recent Advances and Perspectives, in PHARMACEUTICAL RESEARCH, 31(5), 1099-1105.
Novel role of the serine protease inhibitor elafin in gluten-related disorders.
Galipeau Heather J, Wiepjes Michelle, Motta Jean-Paul, Schulz Jessica D, Jury Jennifer, Natividad Jane M, Pinto-Sanchez Ines, Sinclair Daniel, Rousset Perrine, Martin-Rosique Rebeca, Bermudez-Humaran Luis, Leroux Jean Christophe, Murray Joseph A, Smecuol Edgardo, Bai Julio C, Vergnolle Nathalie, Langella Philippe, Verdu Elena F (2014), Novel role of the serine protease inhibitor elafin in gluten-related disorders., in The American journal of gastroenterology, 109(5), 748-56.
Celiac disease: A challenging disease for pharmaceutical scientists
Matoori Simon, Fuhrmann Gregor, Leroux Jean Christophe (2013), Celiac disease: A challenging disease for pharmaceutical scientists, in Pharmaceutical Research, 30(3), 619-626.
Polymer–enzyme conjugates for oral drug delivery applications
Fuhrmann Gregor, Gauthier Marc A., Leroux Jean-Christophe (2013), Polymer–enzyme conjugates for oral drug delivery applications, in Chimia, 67(9), 685-685.
Sustained gastrointestinal activity of dendronized polymer-enzyme conjugates
Fuhrmann Gregor, Grotzky Andrea, Lukic Ruzica, Matoori Simon, Luciani Paola, Yu Hao, Zhang Baozhong, Walde Peter, Schlueter A. Dieter, Gauthier Marc A., Leroux Jean-Christophe (2013), Sustained gastrointestinal activity of dendronized polymer-enzyme conjugates, in NATURE CHEMISTRY, 5(7), 582-589.
Gluten Binden und Spalten – neue adjuvante Therapieansätze für die Zöliakie
Matoori Simon, Fuhrmann Gregor, Leroux Jean-Christophe (2012), Gluten Binden und Spalten – neue adjuvante Therapieansätze für die Zöliakie, in Swiss Medical Forum, 12, 716-717.
In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract.
Fuhrmann Gregor, Leroux Jean-Christophe (2011), In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract., in Proceedings of the National Academy of Sciences of the United States of America, 108(22), 9032-7.

Collaboration

Group / person Country
Types of collaboration
Donald Hilvert Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Elena F. Verdu Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dieter Schlüter, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
18th International Pharmaceutical Technology Symposium Talk given at a conference New trends in biodetoxification 18.09.2016 Antalya, Turkey Leroux Jean-Christophe;
Graphene NOWNANO Summer Conference Talk given at a conference Biodetoxification: from small molecules to sequestering polymers and vesicles 27.06.2016 Manchester, Great Britain and Northern Ireland Leroux Jean-Christophe;
CRS Germany Local Chapter Meeting Talk given at a conference Celiac disease: improving enzymatic oral therapies via polymer conjugation 12.02.2015 Muttenz, Switzerland Leroux Jean-Christophe; Schulz Jessica;
Translational Nanomedicine Talk given at a conference Nanosized therapeutics as sequestering agents 27.08.2014 Angers, France Leroux Jean-Christophe;
IBM Seminar Series Individual talk New approaches in biodetoxification: from small molecules to polymers and vesicles 17.05.2014 Institute of Bioengineering and Nanotechnology, Singapore, Singapore Leroux Jean-Christophe;
11th European Workshop on Particulate Systems in Nanomedicine Talk given at a conference Colloidal approaches to biodetoxification 13.03.2014 Utrecht, Netherlands Leroux Jean-Christophe;
3rd Conference on Innovation in Drug Delivery: Advances in Local Drug Delivery Talk given at a conference Presystemic interventions for the treatment of celiac disease 23.09.2013 Pisa, Italy Leroux Jean-Christophe;
15th International Celiac Disease Symposium 2013 Poster Improving enzymatic oral therapies via site-specific polymer conjugation 22.09.2013 Chicago, United States of America Schulz Jessica;
MRC graduate sysmposium Talk given at a conference Stability of Gluten-cleaving Enzymes in the Gastrointestinal Tract 25.03.2013 Zürich, Switzerland Fuhrmann Gregor;
IDS-FunMat 3rd Training School and Annual Meeting Talk given at a conference Harnessing materials science for biodetoxification 18.03.2013 Annecy, France Leroux Jean-Christophe;
Nanomedicines: from molecules to diagnosis and therapy Talk given at a conference Nanopharmaceutics as sequestering agents 01.10.2012 Rome, Italy Leroux Jean-Christophe;
Fall meeting of the Swiss Chemical Society Poster In vivo imaging of oral enzyme activity in the gastrointestinal tract – application to celiac disease 12.09.2012 Zürich, Switzerland Fuhrmann Gregor;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Seminar Helmholtz Institute Saarbrücken Talk 13.11.2012 Saarbrücken, Germany Leroux Jean-Christophe;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Brot ohne Schmerzen geniessen NZZ German-speaking Switzerland 2013
Media relations: print media, online media Polymers protect enzymes ETH Life International 2013

Awards

Title Year
ETH medal for outstanding doctoral thesis 2014
Rottendorf award 2013 2013

Associated projects

Number Title Start Funding scheme
138342 Functional nanomedicines for improved anticancer chemotherapy 01.05.2012 Project funding (Div. I-III)
124882 Colloidal vesicles for drug detoxification 01.01.2010 Project funding (Div. I-III)

Abstract

Celiac disease (CD) is an inflammatory enteropathy triggered in genetically predisposed individuals by the ingestion of gluten and gluten-like proteins of wheat, rye, and barley. There is increased morbidity and mortality associated with CD. The current and only treatment is life-long elimination of gluten from the diet. This dietary restriction is a difficult experience for many patients and is often associated with a decreased quality of life. Poor compliance, whether inadvertent or voluntary, to a strict gluten-free diet is frequent and predisposes patients to CD complications (e.g., nutritional deficiencies, osteoporosis, secondary autoimmune disorders, malignancies). Hence, there is an urgent need for complementary non-dietary therapies to help treating this common disorder (~1% of the population). CD is induced by immunogenic sequences of gluten proteins which are highly resistant to human digestive proteases. In the gastro-intestinal (GI) tract, a fraction of these peptides reaches the lamina propria, causing a T-cell mediated immune response. One of the most interesting therapeutic options consists in administering to CD patients exogenous enzymes (“glutenases”) that cleave and detoxify the gluten peptides. While promising, this approach is in part limited by the relative lability of the enzymes in the harsh conditions encountered in the GI tract. We believe that conjugation of appropriate polymers to glutenases would be a viable strategy to improve their stability in the stomach and intestine and therefore enhance their efficacy. To validate this hypothesis we have defined the following objectives.1. Characterize the activity and stability of several glutenases under simulated GI conditionsDespite the large number of glutenases described in the literature, there have been very few studies comparing head-to-head the GI stability of these enzymes. We plan to perform such experiments in order to rank glutenase activity under simulated GI conditions, and identify the most stable candidates. These experiments will give us some information about the inactivation process of the enzymes and therefore help establishing the most appropriate stabilization strategies.2. Develop a fluorescence imaging method to study in real time the enzymatic activity in vivoAn important objective of this research is to develop an in vivo fluorescent-based assay that will allow the in situ monitoring of the glutenase activity in real time and help establishing in vitro-in vivo correlations. The assay will rely on the increase in fluorescence intensity that will occur upon the cleavage of labelled immunogenic-like peptide sequences. 3. Synthesize and characterize polymer-conjugated glutenasesBased on the route of inactivation of the glutenases, the enzymes will be modified with polymers to improve their stability. Polymers with diverse structures and functionalities will also be screened to introduce mucoadhesive properties, which could increase the residence time of the conjugates in the upper part of the GI tract. This approach could prove valuable for glutenases that are less active at higher pH or rapidly inactivated by bile salts or intestinal enzymes.4. Study the stability and bioadhesion of the polymer-conjugated glutenases in the GI tractConjugated glutenases showing improved GI resistance in vitro will be evaluated in rats for their bioadhesive properties and ability to degrade specific immunogenic sequences of gluten. The polymer-enzyme transit in the GI tract and the in vivo enzymatic activity will be monitored by in vivo fluorescence imaging techniques.5. Evaluate the efficacy of the polymer-conjugated glutenases in a mouse model of gluten sensitivityThe last step of this work will aim at demonstrating that polymer-conjugated glutenases are better detoxifying agents than their native counterparts. Only in vivo experiments assessing the impact of the treatment on the immune response and effects on the intestinal mucosa can establish whether polymer conjugation is a viable option to improve the therapeutic efficacy of glutenases. These experiments will be performed on a mouse model of gluten-sensitivity.
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