Targeted delivery of therapeutic agents to human adipocytes

A fat cell and therapeutic agent technology, applied in the fields of behenic acid and acylglycine, can solve the problems of poor regeneration of liver cells

Pending Publication Date: 2021-05-14
APTAMIR THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] - Third hit: Hepatocyte dysplasia (fibrosis)

Method used

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  • Targeted delivery of therapeutic agents to human adipocytes
  • Targeted delivery of therapeutic agents to human adipocytes
  • Targeted delivery of therapeutic agents to human adipocytes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] A. Example 1: Single-stranded miRNA (ss-miRNA) analogs with modified structure and length

[0109] Considering the critical role of the seed region (bases 2–8) and the interaction with the Ago2 protein required for the ss-miRNA to function, ss-miRNA analogs of different lengths were prepared including the following chemical modifications: 5' -(E)-vinylphosphonate protection (5'-VP), phosphorothioate (PS) backbone, 2'F, 2'-O-Me and 2'-O-MOE modifications, 5-methyl Modification of cytosine, introduction of a "pyrimidine box", and introduction of a "DNA gap" to make a "gapmer". like Figure 4-Figure 6 shown that either alone (“naked”) or in combination with a lipid tag (e.g., cholesterol or increased-length fatty acids) or a short peptide tag (e.g., hexarelin), the These molecules were tested in primary culture models of the ultimate target of anti-obesity drugs.

Embodiment 2

[0110] B. Example 2: Fatty Acid / miRNA Conjugates

[0111] An extensive "omic" analysis of mature human subcutaneous adipocytes and their exosomes was performed. The present inventors observed high-level expression of fatty acid translocase (FAT, also known as scavenger receptor B3 or CD36), an integral cell membrane transporter involved in the uptake of fatty acids into adipocytes [19, 22-25]. It is expected that combining ss-miRNA analogs with fatty acids naturally transported by FAT will facilitate the targeted delivery of such ss-miRNA analogs to mature adipocytes. This will be demonstrated by synthesizing and validating a series of miRNA analogs covalently linked to fatty acids to facilitate preferential targeting and translocation of adipocyte FAT. These miRNA analogs are referred to herein as AdipomiRs (miRNAs targeting adipocytes).

[0112] AdipomiR synthesis: Fatty acids have been used as chemical penetration enhancers (CPE) for various drugs, including oligonucleotide...

Embodiment 3

[0120] C. Example 3: Hexarelin / miRNA Conjugates

[0121] Recently, hexarelin (a chemically stable and potent growth hormone secretagogue His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH 2 , molecular formula: C 47 h 58 N 12 o 6 , molecular weight: 887) has beneficial effects on fat metabolism via the FAT / CD36 transporter [28, 29], causing fatty acid mobilization and activation of mitochondrial oxidative phosphorylation and thermogenesis. In MKR insulin-resistant mice, hexarelin treatment significantly improved glucose and insulin tolerance and decreased plasma and hepatic triglycerides. Furthermore, the cardioprotective effect of hexarelin is well documented [30].

[0122] Combining ss-miRNA analogs with hexarelin, which is naturally transported by FAT, is expected to facilitate the targeted delivery of such ss-miRNA analogs to mature adipocytes. Therefore, a series of miRNA analogs covalently linked to hexarelin to facilitate preferential targeting of adipocyte FAT was synthesized a...

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Abstract

Compositions and methods relating to modulating thermogenic regulation are disclosed. The compositions and methods can be used to treat diseases or conditions such as obesity or cardiometabolic disorders such as type 2 diabetes mellitus, NAFLD and NASH. Compositions include an adipocyte-targeting composition that includes a therapeutic agent capable of modulating thermogenic regulation, a targeting element facilitating cellular uptake and delivery of the therapeutic agent to a targeted adipocyte, and liposomal particles comprising sphingomyelin, DMPC, and cholesterol, wherein the liposomal particles enhance intra-cellular penetration of the therapeutic agent and protect the therapeutic agent from degradation.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 693,025, filed July 2, 2018, and U.S. Provisional Patent Application No. 62 / 810,141, filed February 25, 2019, which are incorporated by reference in their entirety The content is incorporated into this article in its entirety. [0003] Background of the invention [0004] I.Technical field [0005] The present invention generally relates to compositions comprising therapeutic agents, such as oligonucleotide therapeutics such as microRNA analogs, small molecules, peptides, peptidomimetics, nutraceuticals, or gene editing systems, and the delivery of such therapeutic agents to fat Cells are used in methods of treating human obesity and related cardiometabolic disorders including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). [0006] II. Background technology [0007] Obesity a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/498A61K31/5575A61K39/395
CPCA61K31/713A61K31/609A61K31/05A61K31/12A61K9/127A61K31/20A61K9/0019C12N15/113C12N15/111C12N2310/141C12N2310/14C12N2310/3515C12N2320/32C12N2310/3513A61K47/24A61K47/28A61K31/7105A61K47/542A61K47/6911A61K47/6913A61K47/64A61P29/00A61P3/10A61P9/00A61K47/543A61K31/7088
Inventor 马克·蒂博尼尔
Owner APTAMIR THERAPEUTICS
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