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Compositions and methods of treatment using nicotinamide mononucleotide

A single nucleotide, nicotinamide technology, applied in biochemical equipment and methods, chemical instruments and methods, introduction of foreign genetic material using vectors, etc., can solve the problems of unidentified Slc12a8 function, undisclosed and other problems

Pending Publication Date: 2020-04-10
UNIV OF WASHINGTON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Gagnon et al. did not identify the function of Slc12a8
Kubo, Y. et al. Exp.EyeRes., 124, 17-23, 2014) identified Slc12a8 as a spermine transporter but did not disclose its involvement in NMN transport

Method used

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  • Compositions and methods of treatment using nicotinamide mononucleotide
  • Compositions and methods of treatment using nicotinamide mononucleotide
  • Compositions and methods of treatment using nicotinamide mononucleotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0330] This example illustrates the identification of NMN transporter genes.

[0331] When NAMPT-mediated NAD+ biosynthesis was inhibited by FK866, a potent NAMPT inhibitor, co-administered NMN always produced NAD+ compared to NMN-induced NAD+ in the absence of FK866 in various types of primary cells Higher NAD+ increase (Revollo, J.R. et al., Cell Metab., 6, 363-375, 2007; Stein, L.R. and Imai, S., EMBO J., 33, 1321-1340 2014; Yoshino, J. et al., Cell Metab. ., 14, 528-536, 2011). The present investigators performed gene expression profiling in FK866-treated primary mouse hepatocytes, pancreatic islets, and hippocampal neurospheres to look for genes that were generally upregulated in these three primary cultures. The search focused on genes encoding transporters or transmembrane proteins and found only one gene with unknown function that met these criteria. This gene, Slc12a8, exhibited Z ratios of 2.06, 1.69 and 4.91 in primary hepatocytes, islets and neurospheres, respect...

Embodiment 2

[0333] This example illustrates the differential expression of Slc12a8 in B6 mice.

[0334] figure 2 It shows that Slc12a8 is highly expressed in small intestine and pancreas, and moderately expressed in liver and white adipose tissue in 3-month-old B6 male mice (n=3 mice). Additional Slc12a8 mRNA expression changes were observed in primary mouse hepatocytes, as image 3Shown; (n=4 mice), NIH3T3 fibroblasts (n=4), and explants of jejunum and ileum (DMSO and FK866, n=4 mice, respectively; for FK866 plus NMN, n= 3 mice) were treated with 0.1% DMSO, FK866 alone or FK866 plus NMN (24 hours for cells; 4 hours for explants; analysis by ANOVA using Tukey's test). When treated with FK866, Slc12a8 expression was significantly induced in mouse primary hepatocytes, mouse NIH3T3 fibroblasts, and explants of jejunum and ileum, whereas addition of NMN inhibited this induction ( Figures 3 to 5 ). Figure 4 Intracellular NAD+ content in primary mouse hepatocytes and NIH3T3 fibroblasts t...

Embodiment 3

[0336] This example illustrates the effect of Slc12a8 on the kinetics of NMN uptake.

[0337] Determination of the kinetics of NMN uptake in primary mouse hepatocytes. AOPCP (adenosine-5′-[α,β-methylene] diphosphate) inhibits the extracellular degradation of NMN to NR by CD73. Dipyridamole inhibits the uptake of NR into cells by nucleoside transporters, whereas FK866 inhibits the intracellular NMN synthesis of NAMPT. Intact primary hepatocytes were incubated with AMP or AMP plus AOPCP. Extracellular adenosine production was measured by HPLC at different time points (0, 1, 5, 15 and 30 minutes). AOPCP inhibits 5'-nucleotidase activity by 97%. The mixture of AOPCP, dipyridamole and FK866 did not affect cell viability for up to 30 minutes (data not shown).

[0338] Primary mouse hepatocytes were pretreated with 500 nM FK866 for 24 hours and then incubated with a mixture of 20 μM dipyridamole, 500 μM AOPCP and 500 nM FK866 with or without 100 μM NMN. NMN was measured by HPLC ...

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Abstract

Various methods and compositions for treating age-associated conditions and other medical conditions, such as muscle diseases, type 2 diabetes, and / or obesity are described. Methods of enhancing cellular uptake of NMN and stimulating NAD+ production are further described. Various mammalian cells and mammalian cell lines are described including those comprising a cDNA encoding a Slcl2a8 protein. Gene therapy vectors comprising a nucleic acid encoding Slcl2a8 and non- human animals comprising an inactivating mutation in a Slcl2a8 gene are also disclosed. Also described are methods for screeninga candidate compound to identify compounds that promote NMN transport.

Description

[0001] Statement of Government Support [0002] This invention was made with government support under AG047902 and AG037457 awarded by the National Institutes of Health. The government has certain rights in this invention. [0003] Sequence Listing Citation [0004] Sequence listings are part of this disclosure and include text files containing primers, nucleotide and / or amino acid sequences of the invention. The subject matter of the Sequence Listing is hereby incorporated by reference in its entirety. Information recorded in computer readable form is the same as a written sequence listing. technical field [0005] The present disclosure relates to various methods and compositions for the treatment of age-related disorders and other medical conditions such as muscle disorders, type 2 diabetes and / or obesity. Methods of enhancing cellular uptake of NMN and stimulating NAD+ production are further described. A variety of mammalian cells and mammalian cell lines are describe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/706A61K9/00
CPCA61K45/06A61K31/4406A61K31/706A01K67/0276A01K2217/075A01K2227/105A01K2267/03C12N2740/16043C07K14/705A61K2300/00A61K31/455A61K48/005A61P21/00A61P3/10A61P3/04C12N15/86C12N2740/15032C12N2740/15043G01N33/5008G01N33/6803
Inventor 今井真一郎A·格罗齐奥
Owner UNIV OF WASHINGTON
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