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Oral enzyme therapies for Celiac Sprue.

Gass, Jonathan David.

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Oral enzyme therapies for Celiac Sprue.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Oral enzyme therapies for Celiac Sprue./
作者:	Gass, Jonathan David.
面頁冊數:	192 p.
附註:	Adviser: Chaitan Khosla.
Contained By:	Dissertation Abstracts International68-02B.
標題:	Engineering, Chemical. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3253483

Oral enzyme therapies for Celiac Sprue.
Gass, Jonathan David.

Oral enzyme therapies for Celiac Sprue. - 192 p.

Adviser: Chaitan Khosla.

Thesis (Ph.D.)--Stanford University, 2007.

Celiac Sprue is a multifactorial disease characterized by an inflammatory response to ingested gluten in the small intestine. Proteolytically resistant, proline- and glutamine-rich gluten peptides from wheat, rye and barley persist in the intestinal lumen, and elicit an immune response in genetically susceptible individuals. A strict, lifelong gluten-free diet is the only treatment. Proline- and glutamine-specific endoproteases ("glutenases") are potential therapeutic agents due to their ability to digest gluten epitopes. The objective of this thesis was to develop a protein therapeutic for oral delivery for the treatment of celiac disease. A drug candidate must digest proteolytically-resistant gluten oligopeptides, be stable in the gastrointestinal tract, and be produced at a suitable scale for inexpensive manufacturing.Subjects--Topical Terms:

1018531
Engineering, Chemical.

Oral enzyme therapies for Celiac Sprue.
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245 1 0 $a Oral enzyme therapies for Celiac Sprue.
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500 $a Adviser: Chaitan Khosla.
500 $a Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 1133.
502 $a Thesis (Ph.D.)--Stanford University, 2007.
520 $a Celiac Sprue is a multifactorial disease characterized by an inflammatory response to ingested gluten in the small intestine. Proteolytically resistant, proline- and glutamine-rich gluten peptides from wheat, rye and barley persist in the intestinal lumen, and elicit an immune response in genetically susceptible individuals. A strict, lifelong gluten-free diet is the only treatment. Proline- and glutamine-specific endoproteases ("glutenases") are potential therapeutic agents due to their ability to digest gluten epitopes. The objective of this thesis was to develop a protein therapeutic for oral delivery for the treatment of celiac disease. A drug candidate must digest proteolytically-resistant gluten oligopeptides, be stable in the gastrointestinal tract, and be produced at a suitable scale for inexpensive manufacturing.
520 $a Prolyl endopeptidase from Myxococcus xanthus (MX PEP) was used to develop an efficient manufacturing process. MX PEP was overproduced in E. coli (0.25-0.4 g/L protein) and a simple, scalable purification and lyophilization procedure was established, yielding pure, active enzyme as a dry powder. An in vivo methodology for measuring glutenase efficacy was developed for gluten digestion in rats. EP-B2 (endoprotease B, isoform 2 from Hordeum vulgare) was orally administered to rats with a solid gluten-rich meal. EP-B2 was remarkably effective at solubilizing and digesting gluten in the rat stomach, with no overt signs of toxicity.
520 $a The stability of PEPs in the presence of bile acids and pancreatic enzymes was evaluated as bile acids are present in the intestinal lumen, the intended site for PEP action. Detailed in vitro studies demonstrated that the hydrolysis of PEPS (and select dietary proteins) by pancreatic enzymes is greatly enhanced by bile acids. Due to this instability, a combination enzyme, consisting of glutamine-specific EP-B2 and proline-specific PEP from Sphingomonas capsulata, was developed to digest gluten gastrically. In vitro and in vivo experiments demonstrated that EP-B2 proteolyzes complex gluten proteins in bread, whereas SC PEP rapidly detoxifies the residual oligopeptide products of EP-B2 digestion. By using this two enzyme therapy, it should be possible to increase the safe threshold of ingested gluten, thereby ameliorating the burden of a highly restricted diet for celiac patients.
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