Advertisement

Pharmaceutical Research

, Volume 30, Issue 3, pp 619–626 | Cite as

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

  • Simon Matoori
  • Gregor Fuhrmann
  • Jean-Christophe Leroux
Perspective

ABSTRACT

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains that affects ~1% of the white ethnic population. In the last decades, a rise in prevalence of CD has been observed that cannot be fully explained by improved diagnostics. Genetic predisposition greatly influences the susceptibility of individuals towards CD, though environmental factors also play a role. With no pharmacological treatments available, the only option to keep CD in remission is a strict and permanent exclusion of dietary gluten. Such a gluten-free diet is difficult to maintain because of gluten’s omnipresence in food (e.g., additive in processed food). The development of adjuvant therapies which would permit the intake of small amounts of gluten would be desirable to improve the quality of life of patients on a gluten-free diet. Such therapies include gluten-degrading enzymes, polymeric binders, desensitizing vaccines, anti-inflammatory drugs, transglutaminase 2 inhibitors, and HLA-DQ2 blockers. However, many of these approaches pose pharmaceutical challenges with respect to drug formulation and stability, or application route and dosing interval. This perspective article discusses how pharmaceutical scientists may deal with these challenges and contribute to the implementation of novel therapeutic options for patients with CD.

KEY WORDS

adjuvant therapy autoimmune disorder celiac sprue drug formulation polymeric drug 

ABBREVIATIONS

APC

antigen-presenting cell

CD

celiac disease

GFD

gluten-free diet

GI

gastrointestinal

HLA

human leukocyte antigen

IEL

intraepithelial lymphocyte

IgA

immunoglobulin A

IL-15

interleukin-15

P(HEMA-co-SS)

poly(hydroxyethylmethacrylate-co-styrene sulfonate)

PEP

prolyl endopeptidase

TfR

transferrin receptor

TG2

transglutaminase 2

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

Financial support from the Swiss National Science Foundation (310030_135732) and “IG Zöliakie der Deutschen Schweiz” is acknowledged. Dr. Marc A. Gauthier is acknowledged for his critical reading of the manuscript.

J.-C. Leroux has a consultancy agreement with BioLineRx. The remaining authors disclose no conflicts of interest.

REFERENCES

  1. 1.
    Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PHR, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2012. doi: 10.1136/gutjnl-2011-301346.
  2. 2.
    Tack GJ, Verbeek WHM, Schreurs MWJ, Mulder CJJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol. 2010;7(4):204–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol. 2002;2(9):647–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Catassi C, Kryszak D, Bhatti B, Sturgeon C, Helzlsouer K, Clipp SL, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010;42(7):530–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rewers M, Eisenbarth GS. Autoimmunity: celiac disease in T1DM-the need to look long term. Nat Rev Endocrinol. 2012;8(1):7–8.CrossRefGoogle Scholar
  7. 7.
    Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009;373(9673):1480–93.PubMedCrossRefGoogle Scholar
  8. 8.
    Pinier M, Fuhrmann G, Verdu E, Leroux J-C. Prevention measures and exploratory pharmacological treatments of celiac disease. Am J Gastroenterol. 2010;105(12):2551–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Ciccocioppo R, Di Sabatino A, Corazza GR. The immune recognition of gluten in coeliac disease. Clin Exp Immunol. 2005;140(3):408–16.PubMedCrossRefGoogle Scholar
  10. 10.
    Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297(5590):2275–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut. 2012;61(9):1355–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42(1):71–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Lebreton C, Ménard S, Abed J, Moura IC, Coppo R, Dugave C, et al. Interactions among secretory immunoglobulin A, CD71, and transglutaminase-2 affect permeability of intestinal epithelial cells to gliadin peptides. Gastroenterology. 2012;143(3):698–707.PubMedCrossRefGoogle Scholar
  14. 14.
    Molberg Ø, McAdam S, Lundin KEA, Kristiansen C, Arentz-Hansen H, Kett K, et al. T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol. 2001;31(5):1317–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Di Sabatino A, Vanoli A, Giuffrida P, Luinetti O, Solcia E, Corazza GR. The function of tissue transglutaminase in celiac disease. Autoimmun Rev. 2012;11(10):746–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Meresse B, Malamut G, Cerf-Bensussan N. Celiac disease: an immunological jigsaw. Immunity. 2012;36(6):907–19.PubMedCrossRefGoogle Scholar
  17. 17.
    Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. 2003;362(9377):30–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Abadie V, Discepolo V, Jabri B. Intraepithelial lymphocytes in celiac disease immunopathology. Semin Immunopathol. 2012;34(4):551–66.PubMedCrossRefGoogle Scholar
  19. 19.
    DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature. 2011;471(7337):220–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Sapone A, Bai J, Ciacci C, Dolinsek J, Green P, Hadjivassiliou M, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;10(1):13.PubMedCrossRefGoogle Scholar
  21. 21.
    Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005;128(4):S68–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Sapone A, Lammers K, Casolaro V, Cammarota M, Giuliano M, De Rosa M, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;9(1):23.PubMedCrossRefGoogle Scholar
  23. 23.
    Ahn R, Ding YC, Murray J, Fasano A, Green PHR, Neuhausen SL, et al. Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci. PLoS One. 2012;7(5):e36926.PubMedCrossRefGoogle Scholar
  24. 24.
    Sollid LM, Khosla C. Novel therapies for coeliac disease. J Intern Med. 2011;269(6):604–13.PubMedCrossRefGoogle Scholar
  25. 25.
    Trynka G, Wijmenga C, van Heel DA. A genetic perspective on coeliac disease. Trends Mol Med. 2010;16(11):537–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Lindfors K, Koskinen O, Kaukinen K. An update on the diagnostics of celiac disease. Int Rev Immunol. 2011;30(4):185–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Barratt SM, Leeds JS, Sanders DS. Quality of life in coeliac disease is determined by perceived degree of difficulty adhering to a gluten-free diet, not the level of dietary adherence ultimately achieved. J Gastrointest Liver Dis. 2011;20(3):241–5.Google Scholar
  29. 29.
    Tio M, Cox MR, Eslick GD. Meta-analysis: coeliac disease and the risk of all-cause mortality, any malignancy and lymphoid malignancy. Aliment Pharmacol Ther. 2012;35(5):540–51.PubMedCrossRefGoogle Scholar
  30. 30.
    Stoven S, Murray JA, Marietta E. Celiac disease: advances in treatment via gluten modification. Clin Gastroenterol Hepatol. 2012;10(8):859–62.PubMedCrossRefGoogle Scholar
  31. 31.
    Rashtak S, Murray JA. Review article: coeliac disease, new approaches to therapy. Aliment Pharmacol Ther. 2012;35(7):768–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Keech CL, Dromey J, Chen Z, Anderson RP, McCluskey J. Immune tolerance induced by peptide immunotherapy in an HLA Dq2-dependent mouse model of gluten immunity. Gastroenterology. 2009;136(5):A-57.CrossRefGoogle Scholar
  33. 33.
    Brown GJ, Daveson J, Marjason JK, Ffrench RA, Smith D, Sullivan M, et al. A phase I study to determine safety, tolerability and bioactivity of Nexvax2® in HLA DQ2+ volunteers with celiac disease following a long-term, strict gluten-free diet. Gastroenterology. 2011;140(5):S-437–8.CrossRefGoogle Scholar
  34. 34.
    Daveson AJ, Jones DM, Gaze S, McSorley H, Clouston A, Pascoe A, et al. Effect of hookworm infection on wheat challenge in celiac disease—a randomised double-blinded placebo controlled trial. PLoS One. 2011;6(3):e17366.PubMedCrossRefGoogle Scholar
  35. 35.
    McSorley HJ, Gaze S, Daveson J, Jones D, Anderson RP, Clouston A, et al. Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One. 2011;6(9):e24092.PubMedCrossRefGoogle Scholar
  36. 36.
    Bertrand N, Gauthier MA, Bouvet C, Moreau P, Petitjean A, Leroux J-C, et al. New pharmaceutical applications for macromolecular binders. J Control Release. 2011;155(2):200–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Pinier M, Verdu EF, Nasser-Eddine M, David CS, Vézina A, Rivard N, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology. 2009;136(1):288–98.PubMedCrossRefGoogle Scholar
  38. 38.
    Pinier M, Fuhrmann G, Galipeau HJ, Rivard N, Murray JA, David CS, et al. The copolymer P(HEMA-co-SS) binds gluten and reduces immune response in gluten-sensitized mice and human tissues. Gastroenterology. 2012;142(2):316–25.PubMedCrossRefGoogle Scholar
  39. 39.
    Marti T, Molberg Ø, Li Q, Gray GM, Khosla C, Sollid LM. Prolyl endopeptidase-mediated destruction of T cell epitopes in whole gluten: chemical and immunological characterization. J Pharmacol Exp Ther. 2005;312(1):19–26.PubMedCrossRefGoogle Scholar
  40. 40.
    Stenman SM, Venäläinen JI, Lindfors K, Auriola S, Mauriala T, Kaukovirta-Norja A, et al. Enzymatic detoxification of gluten by germinating wheat proteases: implications for new treatment of celiac disease. Ann Med. 2009;41(5):390–400.PubMedCrossRefGoogle Scholar
  41. 41.
    Fuhrmann G, Leroux J-C. In vitro evaluation of the stability of proline-specific endopeptidases under simulated gastrointestinal conditions. J Control Release. 2010;148(1):e37–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Stepniak D, Spaenij-Dekking L, Mitea C, Moester M, de Ru A, Baak-Pablo R, et al. Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease. Am J Physiol Gastrointest Liver Physiol. 2006;291(4):G621–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Tack GJ, van de Water JM, Kooy-Winkelaar EM, van Bergen J, Meijer GA, von Blomberg BM, et al. Can prolyl endoprotease enzyme treatment mitigate the toxic effect of gluten in coeliac patients? Gastroenterology. 2010;138(5):S-54.CrossRefGoogle Scholar
  44. 44.
    Siegel M, Garber ME, Spencer AG, Botwick W, Kumar P, Williams RN, et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012;57(2):440–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Adelman DC. Gluten degradation by ALV003, a novel drug in development for coeliac disease. 26th AOECS general assembly, international coeliac disease scientific conference—better life for coeliacs. 2012. 6.-9.09.2012, Helsinki, Finland (2012).Google Scholar
  46. 46.
    Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem J. 2004;383(2):311–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Fuhrmann G, Leroux J-C. In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2011;108(22):9032–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Gass J, Ehren J, Strohmeier G, Isaacs I, Khosla C. Fermentation, purification, formulation, and pharmacological evaluation of a prolyl endopeptidase from Myxococcus xanthus: Implications for Celiac Sprue therapy. Biotechnol Bioeng. 2005;92(6):674–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng Des Sel. 2008;21(12):699–707.PubMedCrossRefGoogle Scholar
  50. 50.
    Robic S. Alvine Pharmaceuticals Inc, USA, assignee. PEGylated Glutenase Polypeptides. Patent WO2007047303A2. 2007.Google Scholar
  51. 51.
    Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012;35(1):86–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Leffler DA, Kelly CP, Abdallah HZ, Colatrella AM, Harris LA, Leon F, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol. 2012;107(10):1554–62.PubMedCrossRefGoogle Scholar
  53. 53.
    Ménard S, Lebreton C, Schumann M, Matysiak-Budnik T, Dugave C, Bouhnik Y, et al. Paracellular versus transcellular intestinal permeability to gliadin peptides in active celiac disease. Am J Pathol. 2012;180(2):608–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Mazumdar K, Alvarez X, Borda JT, Dufour J, Martin E, Bethune MT, et al. Visualization of transepithelial passage of the immunogenic 33-residue peptide from α-2 gliadin in gluten-sensitive macaques. PLoS One. 2010;5(4):e10228.PubMedCrossRefGoogle Scholar
  55. 55.
    Siegel M, Khosla C. Transglutaminase 2 inhibitors and their therapeutic role in disease states. Pharmacol Ther. 2007;115(2):232–45.PubMedCrossRefGoogle Scholar
  56. 56.
    Rauhavirta T, Oittinen M, Kivistö R, Männistö P, Garcia-Horsman J, Wang Z, et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol. doi: 10.1007/s10875-012-9745-5.
  57. 57.
    Szondy Z, Sarang Z, Molnár P, Németh T, Piacentini M, Mastroberardino PG, et al. Transglutaminase 2−/− mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci U S A. 2003;100(13):7812–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Hils M, Weber J, Buechold C, Pasternack R. Selective blockers of tissue transglutaminase for coeliac disease therapy. 26th AOECS general assembly, international coeliac disease scientific conference—better life for coeliacs. 2012. 6.-9.09.2012, Helsinki, Finland (2012).Google Scholar
  59. 59.
    van de Wal Y, Kooy YMC, van Veelen P, Vader W, August SA, Drijfhout JW, et al. Glutenin is involved in the gluten-driven mucosal T cell response. Eur J Immunol. 1999;29(10):3133–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Kapoerchan VV, Wiesner M, Overhand M, van der Marel GA, Koning F, Overkleeft HS. Design of azidoproline containing gluten peptides to suppress CD4+ T-cell responses associated with celiac disease. Bioorg Med Chem. 2008;16(4):2053–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Brar P, Lee S, Lewis S, Egbuna I, Bhagat G, Green PHR. Budesonide in the treatment of refractory celiac disease. Am J Gastroenterol. 2007;102(10):2265–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Daum S, Ipczynski R, Heine B, Schulzke JD, Zeitz M, Ullrich R. Therapy with budesonide in patients with refractory sprue. Digestion. 2006;73(1):60–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, et al. Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 2005;52(9):2686–92.PubMedCrossRefGoogle Scholar
  64. 64.
    Šenolt L, Vencovský J, Pavelka K, Ospelt C, Gay S. Prospective new biological therapies for rheumatoid arthritis. Autoimmun Rev. 2009;9(2):102–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Costantino G, della Torre A, Lo Presti MA, Caruso R, Mazzon E, Fries W. Treatment of life-threatening type I refractory coeliac disease with long-term infliximab. Dig Liver Dis. 2008;40(1):74–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275.PubMedCrossRefGoogle Scholar
  67. 67.
    Gauthier MA, Klok H-A. Polymer-protein conjugates: an enzymatic activity perspective. Polym Chem. 2010;1(9):1352–73.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Simon Matoori
    • 1
  • Gregor Fuhrmann
    • 2
  • Jean-Christophe Leroux
    • 3
  1. 1.Department of Chemistry and Applied BiosciencesETH Zurich Institute of Pharmaceutical SciencesZurichSwitzerland
  2. 2.Department of Chemistry and Applied Biosciences, ETH ZurichInstitute of Pharmaceutical SciencesZurichSwitzerland
  3. 3.Department of Chemistry and Applied Biosciences, ETH ZurichInstitute of Pharmaceutical SciencesZurichSwitzerland

Personalised recommendations