Substances for treatment of fatty liver-related conditions

Inventors

Mardinoglu, Adil • Borén, Jan • Uhlén, Mathias

Assignees

Scandibio Therapeutics AB

Abstract

There is provided a composition comprising: A) serine, glycine, betaine, N-acetylglycine, N-acetylserine, dimethylglycine, sarcosine and/or phosphoserine; B) N-acetyl cysteine, cysteine and/or cystine; C) optionally carnitine, deoxycarnitine, gamma-butyrobetaine, 4-trimethylammoniobutanal, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine, N6,N6,N6-trimethyl-L-lysine and/or lysine; and D) nicotinamide riboside, quinolinate, deamino-NAD+, nicotinate D-ribonucleotide, nicotinamide D-ribonucleotide, nicotinate ribonucleoside, nicotinamide and/or nicotinate, wherein the molar ratio of A) to D) is between 250:1 and 1.5:1 and the molar ratio of A) to B) is between 16:1 and 1:4. The composition may be used in a method of treatment of a medical condition selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), type 2 diabetes, obesity, insulin resistance and dyslipidemia.

Core Innovation

The disclosure describes a fatty-liver treatment strategy and compositions that include amino-acid/one-carbon metabolites, thiol/cysteine sources, fatty-acid mitochondrial transport agents, and NAD+-related precursors. In particular, the compositions and treatment schemes are built around serine, N-acetyl cysteine (NAC), and L-carnitine combined with nicotinamide riboside (NR) and/or nicotinamide, with specified molar-ratio constraints between these components. The approach is directed to fatty liver diseases including hepatic steatosis (HS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and alcoholic fatty liver disease (AFLD).

The background and summary identify a problem in NAFLD/HS in which NAD+ and glutathione (GSH) metabolism is altered, and glycine/serine limitation is treated as a key mechanism. The disclosure states that personalized genome-scale metabolic modeling in liver GEM iHepatocytes is used together with metabolomics/kinetics to identify altered NAD+ and GSH metabolism and glycine/serine limitation. This modeling output is then used to support the selection of the amino-acid/one-carbon metabolite group and the NAD+-related precursors, including NR-related compounds.

The disclosure further states validation in mice using an NR/serine/NAC cocktail, where the combination is reported to reduce hepatic triglycerides and improve lipid oxidation. In addition, a proof-of-concept human serine supplementation study is described as reducing liver fat and improving liver enzymes. The embodiments include multiple composition and delivery variations, such as solid vs aqueous suspensions, packaging options, and oral administration, while maintaining the defined molar-ratio constraints among the serine, NAC, L-carnitine, and NR/niacinamide components.

Claims Coverage

The document contains two independent claims. They cover (i) a composition with defined component identities and molar-ratio constraints and (ii) a method of treating a medical condition in a subject using administrations of the same components, also constrained by molar ratios.

Overall, claim coverage centers on using serine plus N-acetyl cysteine plus L-carnitine together with nicotinamide riboside and/or nicotinamide, while enforcing defined molar-ratio constraints between serine and NAD+-related precursor (A:D) and between serine and NAC (A:B). The second independent claim applies these constrained components in a treatment regimen for a medical condition via simultaneous, separate, or sequential administration.

Stated Advantages

Documented Applications