Oral enzyme therapy for celiac sprue.
Celiac sprue is an inflammatory disease of the small intestine caused by dietary gluten and treated by adherence to a life-long gluten-free diet. The recent identification of immunodominant gluten peptides, the discovery of their cogent properties, and the elucidation of the mechanisms by which they engender immunopathology in genetically susceptible individuals have advanced our understanding of the molecular pathogenesis of this complex disease, enabling the rational design of new therapeutic strategies. The most clinically advanced of these is oral enzyme therapy, in which enzymes capable of proteolyzing gluten (i.e., glutenases) are delivered to the alimentary tract of a celiac sprue patient to detoxify ingested gluten in situ. In this chapter, we discuss the key challenges for discovery and preclinical development of oral enzyme therapies for celiac sprue. Methods for lead identification, assay development, gram-scale production and formulation, and lead optimization for next-generation proteases are described and critically assessed.
Division of Biology, California Institute of Technology, Pasadena, California, USA.
Michael T
MT
Bethune
Chaitan
C
Khosla
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D002446:Celiac Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002853:Chromatography, Liquid; D003001:Cloning, Molecular; D055050:Diet, Gluten-Free; D016503:Drug Delivery Systems; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D057487:Enzyme Therapy; D004926:Escherichia coli; D005983:Glutens / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D013058:Mass Spectrometry; D008954:Models, Biological; D008969:Molecular Sequence Data; D015202:Protein Engineering / Q000379:methods*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*
D011994:Recombinant Proteins; D005983:Glutens; D010450:Endopeptidases