Wheat Flour Treatment With Microbial Transglutaminase and Lysine Ethyl Ester: New Frontiers in Celiac Disease Treatment.

NCT ID: NCT02472119

Last Updated: 2015-06-15

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-06-30

Study Completion Date

2015-08-31

Brief Summary

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Celiac disease is one of the most common forms of food intolerance (prevalence 1/200). The disease occurs in genetically predisposed individuals after ingestion of foods containing gluten. Celiac patients can suffer from severe malabsorption syndrome, mainly characterized by diarrhea and weight loss. The only therapeutic approach currently recognized is a life-long gluten-free diet.

Specific regions of gluten molecule become recognizable by lymphocytes and activate them, due to changes made by tissue transglutaminase. These changes consist in the conversion of specific residues of glutamine into glutamic acid. The consequence is an increased binding affinity between gluten and histocompatibility molecule (HLA-DQ2), localized on the surface of the "antigen presenting cells" (APC); the exposure of the fragments of modified gluten on the surface of APC is a phenomenon that eventually activates T lymphocytes.

Recent studies on modified gluten confirmed the hypothesis that it is possible to block the presentation of gluten to lymphocytes by means of lysine ethyl ester binding exclusively to those gluten regions responsible for lymphocyte activation.

The enzymatic treatment is performed directly on flour instead of extracted gluten, maintaining the same anti-inflammatory effectiveness.

The procedure uses a food-grade enzyme, the microbial transglutaminase (mTGasi) isolated from Streptoverticillium mobarensis, able to catalyze the formation of intermolecular "cross-links" that modify the functional properties of the products.

Objective of the study is to validate the ability of the enzyme treatment of wheat flour with mTGasi and lysine ethyl ester to block the toxic effect of gluten in celiac patients.

Detailed Description

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Celiac disease is one of the most common forms of food intolerance (prevalence 1/200). The disease occurs in genetically predisposed individuals after ingestion of foods containing wheat gluten and similar proteins found in other common cereals such as barley and rye. Celiac patients can suffer from severe malabsorption syndrome, mainly characterized by diarrhea, weight loss and growth retardation. The only therapeutic approach currently recognized is a life-long gluten-free diet.

Specific regions of gluten molecule become recognizable by lymphocytes and activate them, due to changes made by tissue transglutaminase. These changes consist in the conversion of specific residues of glutamine (Q) into glutamic acid (E). The consequence is an increased binding affinity between gluten and histocompatibility molecule (HLA-DQ2), localized on the surface of the "antigen presenting cells" (APC); the exposure of the fragments of modified gluten on the surface of APC is a phenomenon that eventually activates T lymphocytes.

Recent studies on modified gluten confirmed the hypothesis that it is possible to block the presentation of gluten to lymphocytes by means of lysine ethyl ester binding exclusively to those gluten regions responsible for lymphocyte activation.

Specifically, it is possible to perform the enzymatic treatment directly on flour instead of extracted gluten, maintaining the same anti-inflammatory effectiveness. The final procedure consists in dissolving the flour in water in the presence of appropriate concentrations of enzyme and lysine ethyl ester, maintaining the suspension in constant motion for two hours at room temperature.

The procedure uses a food-grade enzyme, the microbial transglutaminase (mTGasi) isolated from Streptoverticillium mobarensis, already used for the preparation of food. The mTgasi is able to catalyze the formation of intermolecular "cross-links" modifying the functional properties of the products through the aggregation and polymerization of proteins. The peculiar method identified by our laboratory reduces the possibility of cross-links between proteins: consequently, minimal changes involve the gluten structure and, consequently, the visco-elastic properties of the dough.

Objective of the study is to validate the ability of the enzyme treatment of wheat flour with mTGasi and lysine ethyl ester to block the toxic effect of gluten in celiac patients.

Conditions

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Celiac Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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rusks made with treated flour

Gluten-free diet adding rusks (100g / day) produced with commercial wheat flour enzymatically treated with mTGasi and lysine ethyl ester.

Group Type EXPERIMENTAL

rusks made of wheat flour enzymatically treated

Intervention Type DIETARY_SUPPLEMENT

100 g of rusks obtained from commercial wheat flour enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

Gluten-free diet

Intervention Type DIETARY_SUPPLEMENT

gluten-free diet

rusks made with not-treated flour

Gluten-free diet adding rusks (100g / day) produced with untreated wheat flour.

Group Type ACTIVE_COMPARATOR

rusks made of wheat flour not enzimatically modified

Intervention Type DIETARY_SUPPLEMENT

100 g of rusks obtained from commercial wheat flour NOT enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

Gluten-free diet

Intervention Type DIETARY_SUPPLEMENT

gluten-free diet

Interventions

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rusks made of wheat flour enzymatically treated

100 g of rusks obtained from commercial wheat flour enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

Intervention Type DIETARY_SUPPLEMENT

rusks made of wheat flour not enzimatically modified

100 g of rusks obtained from commercial wheat flour NOT enzymatically treated with mTGasi and lysine ethyl ester, every day for 3 months

Intervention Type DIETARY_SUPPLEMENT

Gluten-free diet

gluten-free diet

Intervention Type DIETARY_SUPPLEMENT

Eligibility Criteria

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Inclusion Criteria

* diagnosis of celiac disease according to ESPGHAN criteria: class III according to Marsh-Oberhuber classification, clear response to gluten-free diet, serological antiendomysium and antitransglutaminase antibodies positive results before GFD;
* HLA DQ2-DQ8 positive results;
* gluten-free diet from at least one year;
* negative serology from at least 1 year;

Exclusion Criteria

* inflammatory bowel diseases;
* tumors;
* infectious liver disease;
* renal impairment.
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Roma La Sapienza

OTHER

Sponsor Role lead

Responsible Party

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Antonio Picarelli

Medical Doctor

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Sapienza University - Policlinico Umberto I

Rome, Italy, Italy

Site Status RECRUITING

Countries

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Italy

Central Contacts

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Antonio Picarelli, medicine

Role: CONTACT

+39 06 49978370

Facility Contacts

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Antonio Picarelli, medicine

Role: primary

+390649978370

References

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Branski D, Fasano A, Troncone R. Latest developments in the pathogenesis and treatment of celiac disease. J Pediatr. 2006 Sep;149(3):295-300. doi: 10.1016/j.jpeds.2006.06.003. No abstract available.

Reference Type BACKGROUND
PMID: 16939736 (View on PubMed)

Nilsen EM, Jahnsen FL, Lundin KE, Johansen FE, Fausa O, Sollid LM, Jahnsen J, Scott H, Brandtzaeg P. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998 Sep;115(3):551-63. doi: 10.1016/s0016-5085(98)70134-9.

Reference Type BACKGROUND
PMID: 9721152 (View on PubMed)

Molberg O, Mcadam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med. 1998 Jun;4(6):713-7. doi: 10.1038/nm0698-713.

Reference Type BACKGROUND
PMID: 9623982 (View on PubMed)

Gianfrani C, Siciliano RA, Facchiano AM, Camarca A, Mazzeo MF, Costantini S, Salvati VM, Maurano F, Mazzarella G, Iaquinto G, Bergamo P, Rossi M. Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology. 2007 Sep;133(3):780-9. doi: 10.1053/j.gastro.2007.06.023. Epub 2007 Jun 20.

Reference Type BACKGROUND
PMID: 17678925 (View on PubMed)

Yokoyama K, Nio N, Kikuchi Y. Properties and applications of microbial transglutaminase. Appl Microbiol Biotechnol. 2004 May;64(4):447-54. doi: 10.1007/s00253-003-1539-5. Epub 2004 Jan 22.

Reference Type BACKGROUND
PMID: 14740191 (View on PubMed)

Fink ML, Chung SI, Folk JE. gamma-Glutamylamine cyclotransferase: specificity toward epsilon-(L-gamma-glutamyl)-L-lysine and related compounds. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4564-8. doi: 10.1073/pnas.77.8.4564.

Reference Type BACKGROUND
PMID: 6107907 (View on PubMed)

Catassi C, Fabiani E, Iacono G, D'Agate C, Francavilla R, Biagi F, Volta U, Accomando S, Picarelli A, De Vitis I, Pianelli G, Gesuita R, Carle F, Mandolesi A, Bearzi I, Fasano A. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007 Jan;85(1):160-6. doi: 10.1093/ajcn/85.1.160.

Reference Type BACKGROUND
PMID: 17209192 (View on PubMed)

Picarelli A, Di Tola M, Sabbatella L, Anania MC, Calabro A, Renzi D, Bai JC, Sugai E, Carroccio A, Di Prima L, Bardella MT, Barisani D, Ribes-Koninckx C, Aliaga ED, Gasparin M, Bravi E; Multicentre Organ Culture System Study Group. Usefulness of the organ culture system in the in vitro diagnosis of coeliac disease: a multicentre study. Scand J Gastroenterol. 2006 Feb;41(2):186-90. doi: 10.1080/00365520510024151.

Reference Type BACKGROUND
PMID: 16509042 (View on PubMed)

Picarelli A, Maiuri L, Frate A, Greco M, Auricchio S, Londei M. Production of antiendomysial antibodies after in-vitro gliadin challenge of small intestine biopsy samples from patients with coeliac disease. Lancet. 1996 Oct 19;348(9034):1065-7. doi: 10.1016/S0140-6736(96)03060-7.

Reference Type BACKGROUND
PMID: 8874458 (View on PubMed)

Marino M, Casale R, Borghini R, Di Nardi S, Donato G, Angeloni A, Moscaritolo S, Grasso L, Mazzarella G, Di Tola M, Rossi M, Picarelli A. The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. Int Immunopharmacol. 2017 Jun;47:1-8. doi: 10.1016/j.intimp.2017.03.012. Epub 2017 Mar 23.

Reference Type DERIVED
PMID: 28343108 (View on PubMed)

Other Identifiers

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672/10 Rif. 1907 / 22.07.2010

Identifier Type: -

Identifier Source: org_study_id

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