Targeted oesophageal administration of zn-alpha2-glycoproteins (zag), methods and formulations thereof

Abstract

The invention provides formulations and methods for ameliorating symptoms associated with metabolic disorders, such as hypoglycemia, obesity, diabetes, and the like by targeted administration to the oesphagus of a subject of Zn-α 2 -glycoproteins or a functional fragment thereof, alone or in combination with additional agents, such as β adrenergin receptor agonists, β adrenergin receptor antagonists, and/or glycemic control agents.

What is claimed is: 
     
         1 . A method of delivering a therapeutic agent to a mammal in need thereof, comprising targeting the therapeutic agent to a receptor in the oesophagus of the subject, wherein the therapeutic agent is zinc-α 2 -glycoprotein (ZAG) or a functional fragment thereof, and is administered in combination with a β3 agonist that specifically targets β3-adrenergic receptor (β3-AR) thereby increasing specific binding of the therapeutic agent to the receptor, thereby delivering the therapeutic agent to the subject. 
     
     
         2 . The method of  claim 1 , wherein the therapeutic agent is administered directly to the oesophagus, or delivered to the oesophagus via oral, buccal, sublingual, or intranasal delivery routes. 
     
     
         3 . The method of  claim 1 , wherein the subject has one or more symptoms associated with muscle wasting, sarcopenia, diabetes, cachexia, muscle loss, lipidystrophy, obesity or overweight, including diseases associated with insulin resistance, hypoglycemia, elevated plasma levels of free fatty acids (NEFA), triglycerides, or glucose. 
     
     
         4 . The method of  claim 1 , wherein the ZAG is mammalian. 
     
     
         5 . The method of  claim 2 , wherein the ZAG is human. 
     
     
         6 . The method of  claim 1 , wherein the mammal is human. 
     
     
         7 . The method of  claim 5 , wherein the ZAG consists of the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         8 . The method of  claim 4 , wherein the ZAG is conjugated to a non-protein polymer comprising sialylated, pegylated, or modified to increase solubility or stability. 
     
     
         9 . The method of  claim 1 , wherein the therapeutic agent is administered in combination with a glycemic reducing agent. 
     
     
         10 . The method of  claim 1 , wherein the therapeutic agent is formulated with one or more of the following: micronutrients, dietary supplements, nutrients, edible compounds and flavorings, excipients selected from the group consisting of phosphate, Tris, arginine, glycine, Tween 80, sucrose, trehalose, mannitol, casein proteins, and derivatives thereof. 
     
     
         11 . A method for increasing a mammal's endogenous expression of a zinc-α 2 -glycoprotein (ZAG), the method comprising administering to the oesophagus of the subject a therapeutic agent, wherein the therapeutic agent is zinc-α 2 -glycoprotein (ZAG) or a functional fragment thereof, in combination with a β3 agonist that specifically targets β3-adrenergic receptor (β3-AR) thereby increasing specific binding of the therapeutic agent to the receptor, thereby increasing the mammal's endogenous expression of ZAG. 
     
     
         12 . The method of  claim 11 , wherein the therapeutic agent is administered directly to the oesophagus, or delivered to the oesophagus via oral, buccal, sublingual, or intranasal delivery routes. 
     
     
         13 . The method of  claim 11 , wherein the mammal has one or more symptoms associated with muscle wasting, sarcopenia, diabetes, cachexia, muscle loss, lipidystrophy, obesity or overweight, including diseases associated with insulin resistance, hypoglycemia, elevated plasma levels of free fatty acids (NEFA), triglycerides, or glucose. 
     
     
         14 . The method of  claim 11 , wherein the ZAG is mammalian. 
     
     
         15 . The method of  claim 12 , wherein the ZAG is human. 
     
     
         16 . The method of  claim 11 , wherein the mammal is human. 
     
     
         17 . The method of  claim 15 , wherein the ZAG consists of the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         18 . The method of  claim 14 , wherein the ZAG is conjugated to a non-protein polymer comprising sialylated, pegylated, or modified to increase solubility or stability. 
     
     
         19 . The method of  claim 11 , wherein the therapeutic agent is administered in combination with a glycemic reducing agent. 
     
     
         20 . The method of  claim 11 , wherein the therapeutic agent is formulated with one or more of the following: micronutrients, dietary supplements, nutrients, edible compounds and flavorings, excipients selected from the group consisting of phosphate, Tris, arginine, glycine, Tween 80, sucrose, trehalose, mannitol, casein proteins, and derivatives thereof.