Glucose glycans for treating urea cycle disorders
Inventors
Gibson, Molly Krisann • Stebbins, Nathan Wilson • Thieroff-Ekerdt, Ruth • VON MALTZAHN, GEOFFREY A.
Assignees
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Publication Number
US-12090168-B2
Publication Date
2024-09-17
Expiration Date
Abstract
Compositions, e.g., pharmaceutical compositions, nutritional compositions, medical foods, and food ingredients, as well as their methods of use, are provided, for treating diseases associated with hyperammonemia, e.g., urea cycle disorders (UCD) and hepatic encephalopathy (HE), e.g., minimal HE (MHE) and overt HE (OHE), and modulating enzyme activities and levels of microbes and taxa, and metabolites (e.g., ammonia) in the microbiome of a subject.
Core Innovation
The invention relates to a method for treating a urea cycle disorder (UCD) in a subject by administering a glycan preparation in an amount effective and for a time sufficient to treat the UCD. The glycan preparation comprises glu100, glu50gal50, or man52glu29gal19, and is defined by quantitative structural and compositional parameters of glycan polymers.
The glycan polymers have an average degree of branching (DB) between 0.1 and 0.4, and at least 50% have a degree of polymerization (DP) of at least 3 and less than 10 glycan units. The average DP is between about DP4 and about DP12, and the ratio of alpha- to beta-glycosidic bonds is between about 1:1 and about 3:1.
Further constraints specify between 20 mol % and 60 mol % 1,6 glycosidic bonds and between 5 mol % and 25 mol % of at least one, two, or three of 1,2; 1,3; and 1,4 glycosidic bonds. The glycan preparation is additionally constrained by either a final solubility limit in water of at least about 70 Brix at 23°C or a dietary fiber content of at least 70%, including combinations of these constraints.
Claims Coverage
The consolidated content provides one independent method claim directed to treating a urea cycle disorder (UCD) by administering a specifically defined glycan preparation. The claim includes nine inventive features defined by glycan identity, quantitative structural and compositional constraints, and solubility limit in water or dietary fiber content, including combinations thereof.
Administering a glycan preparation to treat a urea cycle disorder
A method for treating a urea cycle disorder (UCD) in a subject, comprising administering a glycan preparation in an amount effective and for a time sufficient to treat the UCD.
Glycan unit composition selected from glu100, glu50gal50, or man52glu29gal19
The glycan preparation comprises glu100, glu50gal50, or man52glu29gal19.
Average degree of branching within 0.1 to 0.4
The average degree of branching (DB) of the glycan polymers in the glycan preparation is between 0.1 and 0.4.
Polymer degree of polymerization distribution with 50% between 3 and <10 units
At least 50% of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 10 glycan units.
Mean degree of polymerization between about DP4 and about DP12
The average DP of the glycan preparation is between about DP4 and about DP12.
Alpha to beta glycosidic bond ratio between about 1:1 and about 3:1
The ratio of alpha- to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is between about 1:1 and about 3:1.
1,6 glycosidic bonds at 20 mol% to 60 mol%
The glycan preparation comprises between 20 mol % and 60 mol % 1,6 glycosidic bonds.
1,2/1,3/1,4 glycosidic bonds fraction between 5 mol% and 25 mol%
The glycan preparation comprises between 5 mol % and 25 mol % of at least one, two, or three of 1,2; 1,3; and 1,4 glycosidic bonds.
Solubility limit in water constraint of at least about 70 Brix at 23°C or dietary fiber content at least 70%
The glycan preparation has a final solubility limit in water of at least about 70 Brix at 23°C, or a dietary fiber content of at least 70%, or combinations of these constraints.
Overall, the claim coverage centers on a single independent treatment method in which a subject with UCD is treated by administering a glycan preparation defined by specific glycan compositions and quantitative parameters including DB, DP distribution, mean DP, alpha-to-beta glycosidic bond ratio, quantified glycosidic bond fractions, and either solubility limit in water or dietary fiber content constraints.
Stated Advantages
Treats a urea cycle disorder (UCD) in a subject.
Reduces hyperammonemia by leveraging microbiome/modulating effects on ammonia and related metabolites and enzymatic activities.
Reduces ammonia levels in the gut in a UCD context, including at least a 10% reduction compared to a predetermined or reference level.
Documented Applications
Treating urea cycle disorders (UCD), including hyperammonemia, in a subject.
Treating hepatic encephalopathy (including minimal hepatic encephalopathy and overt hepatic encephalopathy) in the context described in the partial content.
Ex vivo fecal slurry experiments showing selected glycans reduce ammonia.
Gut microbiome modulation across colon regions and links to ammonia reduction, including taxonomic associations such as Bacteroides abundance with ammonia reduction.
Treatment of a urea cycle disorder (UCD) in a subject by administering a glycan preparation with specified glycan structural and composition properties.
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