Compositions and methods for modulating serum cholesterol

a technology of serum cholesterol and compositions, applied in the direction of peptide/protein ingredients, metabolism disorders, instruments, etc., can solve the problems of incomplete characterization of tnf- receptors, significant side effects, and cholesterol uptake, so as to enhance the activity of ldl receptors, enhance the selectivity and effectiveness of testing, and enhance the production of ldl receptors

Inactive Publication Date: 2005-04-14
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038] Significantly, use of multiple testing strategies (e.g., a combination of one in vitro and / or in vivo assays) with a single anti-lipemic drug can extend the selectivity and effectiveness of the testing as needed. That is, the testing strategy can be tailored for treatment or prevention of a particular cholesterol related disease or group of patients if required.
[0039] Such broad spectrum testing provides additional advantages. For example, preferred anti-lipemic drugs have capacity to enhance LDL receptor activity (typically by enhancing production of the LDL receptor) and provide for a reduction in serum cholesterol level. Thus by providing such dual “anti-cholesterol” activity, the invention is a significant advance over prior therapies and agents that have been reported to reduce serum cholesterol in one way, usually by targeting cholesterol biosynthesis. Accordingly, preferred anti-lipemic drugs of this invention feature better activity, can be administered at lower dosages then prior agents. Patient tolerance of the anti-lipemic drugs will also be positively impacted.

Problems solved by technology

For example, there has been recognition that cells with enough cholesterol do not make sufficient LDL receptors, thereby reducing or even blocking uptake of cholesterol by the cell.
However, the TNF-α receptor remains incompletely characterized.
Although some clinical benefit has been reported to follow use of these and other serum lowering agents, there have been reports of significant side-effects.
Unfortunately, requisite drugs for such high throughput screening assays are not widespread.
A significant reason for lack of progress in this area is insufficient understanding of molecules (i.e. effectors) that impact SREP-1 and the LDL receptor.

Method used

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  • Compositions and methods for modulating serum cholesterol
  • Compositions and methods for modulating serum cholesterol
  • Compositions and methods for modulating serum cholesterol

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Effect of TNF-α on Neutral Sphingomyelinase Activity

[0146] Neutral sphingomyelinase activity increased rapidly with the addition of TNF-a. See FIG. 1. A maximal 2.5 fold increase in activity was observed 15 minutes after TNF-α was added to the cells. The gradual return of N-SMase activity to control levels within 1 hour contrasted the rapid onset of activation and is reflected in the asymmetric kinetic profile observed.

[0147]FIG. 1 illustrates the effect of TNF-α on neutral sphingomyelinase activity and is explained in more detail as follows: Confluent cultures of HH-25 cells were washed once with PBS and incubated in serum free media for 30 minutes prior to the addition of TNF-α (10 ng / ml). At the indicated time, cells were harvested in PBS, pelleted and frozen. Cells were subsequently lysed as described in materials and methods. N-SMase assays were performed in duplicate as described. Error bars represent±one standard deviation from the mean.

example 2

Kinetics of SREBP-1 Proteolysis

[0148] Sterol independent SREBP-1 maturation in response to TNF-α closely paralleled the kinetics of TNF-α induced N-SMase activation. The mass of the mature form of SREBP-1 was found to increase 2 fold after 5 minutes and 3 fold after 15 minutes of incubation with TNF-α. See FIG. 2A. The amount of mature SREBP-1 returned to control levels within one hour. This effect could not be recapitulated with EGF or PDGF treatment. The increase in mature SREBP-1 levels was accompanied by a concomitant decrease in the intensity of the band corresponding to the precursor form of SREBP-1. See FIG. 2B. After 60 minutes of treatment significantly less precursor SREBP-1 was visible.

[0149] To incorporate the observed increase in mature SREBP-1 and the concomitant decrease in precursor SREBP-1 into a single variable, the ratio of precursor SREBP-1 to mature was plotted. See FIG. 2B. A maximal 1.5 fold decrease in the precursor to mature ratio occurred 45 minutes after...

example 3

Effects of TNF-α, Sphingomyelinase and C2-ceramide on Apoptosis in Hepatocytes

[0155] To demonstrate that the observed maturation of SREBP-1 was not an artifact of the more general phenomenon of apoptosis induced proteolysis we performed DNA laddering assays. The 160 bp DNA ladder characteristic of cells undergoing apoptosis was not observed in any of the samples.

[0156] TNF-α, C2-ceramide and sphingomyelinase did not induce apoptosis demonstrating that in hepatocytes, SREBP-1 maturation is not part of the more general phenomenon of apoptotic protein hydrolysis.

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Abstract

Compositions and methods are provided for modulating serum cholesterol in a subject mammal. In one aspect, the invention features novel anti-lipemic drugs that include at least one identified effector of the Low Density Lipoprotein (LDL) receptor and at least one identified serum cholesterol inhibitor. In a particular aspect, the drugs include one identified sphingolipid or protein modifying same linked to one identified serum cholesterol inhibitor. Additionally provided are methods for identifying anti-lipemic drugs capable of modulating the LDL receptor and specifically SREBP-1 maturation, including assays designed to identify pharmacological drugs capable of stabilizing or reducing serum cholesterol levels in a mammal and particularly a human patient.

Description

[0001] This application claims the benefit of U.S. provisional application No. 60 / 121,447, filed Feb. 24, 1999, which is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT INTEREST [0002] Funding for the present invention was provided in part by the Government of the United States by virtue of National Institute of Health Grants R0-1 DK-31722 and P50-HL4812. Thus, the Government of the United States has certain rights in and to the invention claimed herein.FIELD OF THE INVENTION [0003] The present invention relates to compositions and methods for modulating serum cholesterol. In one aspect, the invention features novel anti-lipemic drugs that include at least one identified effector of the Low Density Lipoprotein (LDL) receptor and at least one identified serum cholesterol inhibitor. In a particular aspect, the anti-lipemic drug includes at a sphingolipid or protein modifying same linked to the serum cholesterol inhibitor. Additionally provided are methods for ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/46A61K38/57G01N33/92
CPCG01N33/92G01N2800/044A61K38/1709A61K31/164A61K2300/00
Inventor CHATTERJEE, SUBROTO
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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