Rational design of combination enzyme therapy for celiac sprue.
Celiac sprue (also known as celiac disease) is an inheritable, gluten-induced enteropathy of the upper small intestine with an estimated prevalence of 0.5%-1% in most parts of the world. The ubiquitous nature of food gluten, coupled with inadequate labeling regulations in most countries, constantly poses a threat of disease exacerbation and relapse for patients. Here, we demonstrate that a two-enzyme cocktail comprised of a glutamine-specific cysteine protease (EP-B2) that functions under gastric conditions and a PEP, which acts in concert with pancreatic proteases under duodenal conditions, is a particularly potent candidate for celiac sprue therapy. At a gluten:EP-B2:PEP weight ratio of 75:3:1, grocery store gluten is fully detoxified within 10 min of simulated duodenal conditions, as judged by chromatographic analysis, biopsy-derived T cell proliferation assays, and a commercial antigluten antibody test.
Siegel
Matthew
M
Department of Chemical Engineering, Stanford University, Stanford, California 94305, USA.
Bethune
Michael T
MT
Gass
Jonathan
J
Ehren
Jennifer
J
Xia
Jiang
J
Johannsen
Alexandre
A
Stuge
Tor B
TB
Gray
Gary M
GM
Lee
Peter P
PP
Khosla
Chaitan
C
D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000201:enzymology* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation; D002469:Cell Separation; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D005417:Flavobacterium / Q000201:enzymology / Q000235:genetics; D005983:Glutens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008969:Molecular Sequence Data; D016941:Myxococcus xanthus / Q000201:enzymology / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D000939:Epitopes; D011498:Protein Precursors; D005983:Glutens; D003546:Cysteine Endopeptidases