Pharmaceutical preparation of carbohydrates for therapeutic use

Abstract

The disclosure provides methods for preparation of carbohydrate replacement therapies (CRT) that include nanocarriers of carbohydrates and glycolipids for pharmaceutical delivery to cell interior, endoplasmic reticulum, and Golgi for treating CDG type I and CDG type II diseases as well as other metabolic disorders.

1 . A composition comprising:
 a lipid particle; and   an endogenous carbohydrate encapsulated in the lipid particle,   wherein the lipid particle comprises a molecule capable of minimizing degradation of the lipid particle, enhancing retention of the lipid particle, and/or making the lipid particle immunotolerant when administered to a subject in need thereof.   
     
     
         2 . The composition of  claim 1 , wherein the molecule is ethylene oxide, an ethylene oxide oligomer, an ethylene oxide polymer, polyethylene glycol (PEG), a PEGylated neutral lipid, or any combination thereof. 
     
     
         3 . The composition of  claim 2 , wherein the lipid particle further comprises a lipid selected from the group consisting of a phospholipid, a glycerolipid, a sphingolipid, and any combination thereof. 
     
     
         4 . The composition of  claim 3 , wherein the lipid has a polar head group. 
     
     
         5 . The composition of  claim 4 , wherein the polar head group comprises choline, ethanolamine, serine, glycerol, inositol, or any combination thereof. 
     
     
         6 . The composition of  claim 1 , wherein the lipid particle further comprises phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), or any combination thereof. 
     
     
         7 . The composition of  claim 1 , wherein the lipid particle further comprises cholesterol, a fatty acid, or a combination thereof. 
     
     
         8 . The composition of  claim 1 , wherein the lipid particle is selected from the group consisting of a liposome, a micelle, a solid lipid nanoparticle, and a niosome. 
     
     
         9 . The composition of  claim 1 , wherein the endogenous carbohydrate is selected from the group consisting of a monosaccharide, a phosphorylated monosaccharide, a disaccharide, a phosphorylated disaccharide, an oligosaccharide, a phosphorylated oligosaccharide, a polysaccharide, a phosphorylated polysaccharide, mannose, a phosphorylated mannose, a mannofuranose, a phosphorylated mannofuranose, a mannopyranos, a phosphorylated mannopyranos, mannose-1-phosphate, a nucleotide sugar, a uridine diphosphate, a guanine diphosphate, a cytosine monophosphate, fucose, GDP-fucose, a sialic acid, CMP-sialic acid, N-acetylneuraminic acid (Neu5Ac), and CMP-Neu5Ac. 
     
     
         10 . The composition of  claim 1 , wherein the composition, when administered to a subject in need thereof, induces at least a 0.05-fold to at least a 3-fold increase in cellular production of higher-order lipid-linked oligosaccharides in the subject, as compared to cellular production of higher-order lipid-linked oligosaccharides in the subject in the absence of administering the composition to the subject. 
     
     
         11 . The composition of  claim 10 , wherein the higher-order lipid-linked oligosaccharides comprise Man4GlcNAc2, Man5GlcNAc2, Man6GlcNAc2, Man7GlcNAc2, Man8GlcNAc2, Man9GlcNAc2, or any combinations thereof. 
     
     
         12 . A composition comprising:
 a liposome; and   mannose-1-phosphate encapsulated in the liposome,   wherein the liposome comprises cholesterol and phosphatidylethanolamine (PE) attached to polyethylene glycol (PEG).   
     
     
         13 . A pharmaceutical composition comprising the composition of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         14 . A method for delivering a carbohydrate to a subject in need thereof, comprising administering to the subject the composition of  claim 1 . 
     
     
         15 . A method for delivering a carbohydrate to a cell interior of a subject in need thereof, comprising administering to the subject the composition of  claim 1 ,
 wherein the administered composition traverses the cell plasma membrane to deliver the carbohydrate to the cell interior.   
     
     
         16 . A method for treating a congenital disorder of glycosylation (CDG) in a subject in need thereof, comprising administering to the subject the composition of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the congenital disorder of glycosylation (CDG) is a CDG-Ia disorder. 
     
     
         18 . The method of  claim 14 , wherein administration of the composition induces at least a 0.05-fold to at least a 2-fold increase in cellular production of higher-order lipid-linked oligosaccharides in the subject, as compared to cellular production of higher-order lipid-linked oligosaccharides in the subject in the absence of administering the composition to the subject. 
     
     
         19 . The method of  claim 18 , wherein the higher-order lipid-linked oligosaccharides comprise Man4GlcNAc2, Man5GlcNAc2, Man6GlcNAc2, Man7GlcNAc2, and any combination thereof. 
     
     
         20 . The method of  claim 15 , wherein administration of the composition minimizes degradation of the lipid particle, enhances retention of the lipid particle, and/or makes the lipid particle immunotolerant when administered to the subject.