Oligosaccharide compositions and methods of use thereof for reducing ammonia levels
AssigneeKaleido Biosciences, Inc.
InventorsChristopher Matthew Liu, John M. Geremia, Anastasia Lioubomirov, Max Hecht
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Abstract
Aspects of the disclosure relate to oligosaccharide compositions and methods of making the same. Also provided are methods of using oligosaccharide compositions as microbiome metabolic therapies for reducing ammonia levels and for the treatment of hyperammonemia-related diseases (e.g., urea cycle disorders and hepatic encephalopathy).
Claims128
An oligosaccharide composition comprising a plurality of oligosaccharides, the composition being characterized by multiplicity-edited gradient-enhanced 1H-13C heteronuclear single quantum coherence (HSQC) NMR spectrum comprising signals 1, 3, and 4, each signal having properties as set forth in Table 5:
- Center
- Position
- Area under the curve
- Sig-
- (ppm)
- (AUC) (% of total areas
- Glycosidic
- nal
- 1H
- 13C
- of signals of Table 5)
- Bond Type
- 1
- 5.39
- 100.31
- 3.37-4.78
- alpha-1,4
- 3
- 5.35
- 99.77
- 6.64-8.71
- alpha-1,3
- 4
- 5.22
- 102.55
- 0.00-0.95
- —
An oligosaccharide composition comprising a plurality of oligosaccharides, each oligosaccharide comprising a plurality of monomer radicals;
- the plurality of oligosaccharides comprising two or more types of monomer radicals selected from radicals (1)-(7), wherein the selected radicals are present in the plurality of oligosaccharides in a defined molar percentage (mol %) range:
- (1) 2-glucopyranose diradicals, representing 6.15-9.54 mol % of monomer radicals in the plurality of oligosaccharides;
- (2) 6-glucopyranose diradicals, representing at least 18.94 mol % of monomer radicals in the plurality of oligosaccharides;
- (3) 4-glucopyranose diradicals, representing 6.63-8.74 mol % of monomer radicals in the plurality of oligosaccharides;
- (4) 3,4-glucopyranose triradicals, representing less than 1.42 mol % of monomer radicals in the plurality of oligosaccharides;
- (5) 2,3-glucopyranose triradicals, representing 1.01-2.59 mol % of monomer radicals in the plurality of oligosaccharides;
- (6) 3,4,6-glucopyranose tetraradicals, representing less than 1.00 mol % of monomer radicals in the plurality of oligosaccharides;
- and
- (7) 2,4,6-glucopyranose tetraradicals, representing less than 0.72 mol % of monomer radicals in the plurality of oligosaccharides;
- wherein at least one of the two or more types of monomer radicals is (4) or (7).
An oligosaccharide composition comprising a plurality of oligosaccharides, each oligosaccharide comprising a plurality of monomer radicals;
- the plurality of oligosaccharides comprising radicals (1)-(15), wherein the radicals (1)-(15) are present in the plurality of oligosaccharides in a defined molar percentage (mol %) range:
- (1) 2-glucopyranose diradicals, representing 6.15-9.54 mol % of monomer radicals in the plurality of oligosaccharides;
- (2) 6-glucopyranose diradicals, representing at least 18.94 mol % of monomer radicals in the plurality of oligosaccharides;
- (3) 4-glucopyranose diradicals, representing 6.63-8.74 mol % of monomer radicals in the plurality of oligosaccharides;
- (4) 3,4-glucopyranose triradicals, representing less than 1.42 mol % of monomer radicals in the plurality of oligosaccharides;
- (5) 2,3-glucopyranose triradicals, representing 1.01-2.59 mol % of monomer radicals in the plurality of oligosaccharides;
- (6) 3,4,6-glucopyranose tetraradicals, representing less than 1.00 mol % of monomer radicals in the plurality of oligosaccharides;
- (7) 2,4,6-glucopyranose tetraradicals, representing less than 0.72 mol % of monomer radicals in the plurality of oligosaccharides;
- (8) t-glucopyranose monoradicals, representing 26.87-46.98 mol % of monomer radicals in the plurality of oligosaccharides;
- (9) 3-glucopyranose diradicals, representing at least 6.94 mol % of monomer radicals in the plurality of oligosaccharides;
- (10) 2,4-glucopyranose triradicals, representing less than 1.43 mol % of monomer radicals in the plurality of oligosaccharides;
- (11) 2,6-glucopyranose/4,6-glucopyranose triradicals, representing less than 9.66 mol % of monomer radicals in the plurality of oligosaccharides;
- (12) 2,3,4-glucopyranose radicals, representing 0.07-0.85 mol % of monomer radicals in the plurality of oligosaccharides
- (13) 3,6-glucopyranose triradicals, representing 2.35-6.01 mol % of monomer radicals in the plurality of oligosaccharides;
- (14) 2,3,6-glucopyranose tetraradicals, representing 0.06-0.86 mol % of monomer radicals in the plurality of oligosaccharides;
- and
- (15) 2,3,4,6-glucopyranose pentaradicals, representing less than 0.61 mol % of monomer radicals in the plurality of oligosaccharides.
An oligosaccharide composition comprising a plurality of oligosaccharides that comprise Formula (I):
- wherein R is independently selected from hydrogen, and Formulae (Ia), (Ib), (Ic), and (Id):
- wherein R in Formulae (Ia), (Ib), (Ic), and (Id) is independently defined as above in Formula (I);
- wherein the composition is produced by a process comprising:
- (a) forming a reaction mixture comprising a dextrose preparation with a catalyst comprising acidic protons;
- and
- (b) promoting acid catalyzed oligosaccharide formation in the reaction mixture by transferring sufficient heat to the reaction mixture to maintain the reaction mixture at its boiling point until the molar ratio of net water condensate produced by the reaction mixture relative to total dextrose in the dextrose preparation prior to loading in (a) is in a range of 0.35-1.0, wherein the reaction mixture is maintained at a pressure in a range of 0.5-1.5 atm.
The method of any one of claims 109-111, wherein the subject has or has been diagnosed with an infection.
The method of any one claim of 112 or 114, wherein the subject has or has been diagnosed as having a cirrhosis.
A method of producing a oligosaccharide composition comprising a plurality of oligosaccharides, the method comprising:
- (a) heating a dextrose preparation comprising dextrose monomer, under agitation conditions, to a temperature in a range of 120° C. to 145° C.;
- (b) forming a reaction mixture comprising a dextrose preparation comprising dextrose monomer with a catalyst comprising acidic protons, wherein the molar ratio of acidic protons to dextrose monomer is in a range of 0.001-0.25;
- and
- (c) promoting acid catalyzed oligosaccharide formation in the reaction mixture by transferring sufficient heat to the reaction mixture to maintain the reaction mixture at its boiling point until the weight percent of dextrose monomer in the reaction mixture is less than 30%, wherein the reaction mixture is maintained at a pressure in a range of 0.5-1.5 atm.
Dependencies are inferred from the claim text.