Alkaline phosphatase for treating an inflammatory disease of the gastro-intestinal tract
Inventors
Brands, Rudi • Poelstra, Klaas
Assignees
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Publication Number
US-8574863-B2
Publication Date
2013-11-05
Expiration Date
Abstract
The present invention provides a use for alkaline phosphatase for the manufacture of a medicament for the prevention or reduction of toxic LPS influx through a mucosal lining of a mammalian body cavity. A source of alkaline phosphatase is administered for the prophylaxis or treatment of LPS mediated or exacerbated diseases. The invention also provides compositions comprising a source of alkaline phosphatase for the prevention or reduction of (toxic) LPS influx or passage through mucosal layers.
Core Innovation
The invention relates to preventing or reducing LPS toxicity at an intestinal mucosa by administering a composition comprising a source of alkaline phosphatase (AP) suitable for preventing or reducing LPS-induced toxicity at the intestinal mucosa. The approach treats a gastro-intestinal (GI) tract inflammatory disease selected from Crohn's disease, enterocolitis, and ulcerative colitis by delivering the AP to the GI tract of the subject.
The underlying problem described is LPS/endotoxin toxicity and the influx and passage of LPS through mucosal layers. The disclosure connects LPS toxicity to mucosal barrier dysfunction, including enhanced mucosal permeability associated with decreased intestinal perfusion and/or intestinal ischemia, which increases sensitivity of the GI tract to LPS.
The disclosure further describes LPS detoxification/neutralization at the intestinal mucosa, including dephosphorylation of lipid A. It also describes delivery concepts for AP to mucosal sites, including enteric-coated AP for oral delivery to the intestinal mucosa, and additional embodiments directed to targeting mucosal permeability and other mucosal sites.
The disclosure includes documented in vivo examples in mouse colitis models, where oral AP reduces cytokine levels and improves clinical outcomes. It also provides pharmacokinetic and local bioavailability findings in GI segments after oral dosing, supporting delivery and activity in the GI tract and intestinal mucosa.
Claims Coverage
One independent claim is identified. It includes two inventive features: administering an AP source to prevent or reduce LPS toxicity at intestinal mucosa, and treating selected GI inflammatory diseases by delivering AP to the GI tract.
Administering an AP source to prevent or reduce LPS toxicity at intestinal mucosa
A method for preventing or reducing LPS toxicity at an intestinal mucosa in a subject, comprising administering a composition comprising a source of alkaline phosphatase (AP) suitable for preventing or reducing LPS-induced toxicity at the intestinal mucosa.
Treating selected GI inflammatory diseases by delivering AP to the GI tract
The method administers the AP source to the GI tract of a subject suffering from a GI tract inflammatory disease selected from Crohn's disease, enterocolitis, and ulcerative colitis, wherein the AP is delivered to the GI tract to treat said GI tract inflammatory disease.
The independent claim scope centers on delivering an alkaline phosphatase (AP) source to the GI tract to prevent or reduce LPS-induced toxicity at the intestinal mucosa, for subjects with Crohn's disease, enterocolitis, or ulcerative colitis.
Stated Advantages
Preventing or reducing LPS toxicity at an intestinal mucosa.
Treating a GI tract inflammatory disease selected from Crohn's disease, enterocolitis, and ulcerative colitis by delivering AP to the GI tract.
Detoxification/neutralization of LPS at the intestinal mucosa, including dephosphorylation of lipid A.
Oral AP reduces cytokine levels and improves clinical outcomes in mouse colitis models.
Documented Applications
Prophylaxis or treatment of LPS-mediated or LPS-exacerbated GI inflammatory diseases, including Crohn’s disease and ulcerative colitis, by delivering AP to intestinal mucosa.
Use in (necrotizing) enterocolitis and other GI inflammatory disease contexts associated with LPS/endotoxin influx and mucosal permeability.
Use targeting increased mucosal permeability, including situations associated with decreased perfusion or ischemia.
Use directed to other mucosal sites, including respiratory and topical sites.
Use demonstrated in mouse colitis models, including DSS colitis and TNBS colitis, with oral AP reducing cytokine levels and improving clinical outcomes.
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