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Methods of modulating lipid metabolism and storage

a technology of lipid metabolism and modulator, applied in the field of lipid metabolism and storage modulator, can solve the problems of no treatment for lipid metabolism disorders, and no treatment that can potentially eliminate the disorder

Inactive Publication Date: 2005-05-26
CURIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the discovery of a hedgehog-signaling pathway that plays a role in the metabolism of lipids, including regulation of apolipoprotein expression, endogenous cholesterol synthesis, and uptake of exogenous dietary cholesterol. The invention provides methods for using hedgehog modulators, such as antagonists or agonists, to modulate lipid metabolism and storage, and for preventing or treating various lipid metabolism disorders. The technical effects include the development of new methods for treating lipid metabolism disorders and the discovery of a new target for drug development.

Problems solved by technology

Many attempts to treat lipid metabolism disorders have been made with little practical success.
There are currently no treatments that address lipid metabolism disorders by modulating their metabolism at the source, namely, the intestine.
Nor are there any treatments that can potentially eliminate the disorder in and of itself.

Method used

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  • Methods of modulating lipid metabolism and storage
  • Methods of modulating lipid metabolism and storage
  • Methods of modulating lipid metabolism and storage

Examples

Experimental program
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example 1

Materials and Methods

1.1 Animal Housing and Treatment

[0261] Pregnant mice (C57BL / 6 or BALB / c) are either purchased (Jackson Laboratory, Bar Harbor, Me.) or matings set up in the mouse facility at Biogen, Inc. Pregnant mice at E12.5 of gestation are injected with 200 ug antibodies once every two days (6 mg / kg) by i.v. injection. The subsequently born offspring continue to receive injections (3 mg / kg) once every two days intraperitoneally (i.p.) until the time of sacrifice. In some experiments, mice receive injections only after birth (postnatal day 1) and followed the same injection regimens as the prenatal injections described above.

[0262] In experiments with adult mice that receive treatment only postnatally, two groups, each containing twenty (20) BALB / c mice (Jackson Labs, Bar Harbor Me.) were maintained under standard laboratory conditions. The two groups were divided into two main sections, dependent upon treatment. Group A mice are treated with hedgehog antagonist, while g...

example 2

Evaluation of Weight Loss in Mice Subject to the Modulating Effect of a Hedgehog Antagonist

[0269] Three week old BALB / c mice (n=4) and 16 week old BL / 6 mice (n=4) are injected with control 1E6 mab or hedgehog antagonist 5E1 mab (8 mg / kg; three times per week) for 18 weeks. Mice are subject to either chow diet or high fat diet (19.2% fat) from the beginning of antibody treatments. Body weight is measured every week and is shown in FIG. 1 as a percentage of weight change as compared to the first weeks weight post treatment. There is a high-fat diet dependent weight loss only in the anti-hedgehog 5E1 treated group. Lipid accumulation (as evidenced by oil staining) was only observed in this group of mice.

example 3

Evaluation of the Modulating Effect of a Hedgehog Antagonist on Obese Mice

[0270] A strain of obese mice with a leptin gene mutation are obtained from Jackson Laboratory (Bar Harbor, Me.). Six week old obese mice are treated with 1E6 or 5E1 mabs (10 mg / kg; three times per week) for 8 weeks and the body weight measured before each injection (FIG. 2). The body weight is indicated as the percentage of weight change as compared to the original weight of the animal prior to the first injection. Treatment with hedgehog antagonist results in significant weight loss in the obese mice.

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Abstract

Anti-hedgehog antibodies directed at blocking the binding of hedgehog to its receptor patched-1, will impair lipid metabolism and storage. This invention presents methods for the treatment of a variety of lipid metabolism and lipid storage disorders, aberrant apolipoprotein expression, atherosclerosis and other lipid associated disorders using lipid modulators such as hedgehog antagonists or hedgehog agonists.

Description

RELATED APPLICATIONS [0001] This is a continuation of PCT / US00 / 05662 filed on 3 Mar. 2000 as a continuation-in-part of prior U.S. provisional Ser. No. 60 / 122,640 filed on 3 Mar. 1999 and U.S. provisional Ser. No. 60 / 124,446 filed on 15 Mar. 1999. The entire disclosure of each of the aforesaid patent applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention relates generally to methods for modulating the metabolism and storage of lipids. The invention relates particularly to the use of lipid metabolism and storage modulators such as agonists or antagonists of hedgehog activity to alter the metabolism of lipids in the gastrointestinal tract, as well as to alter the storage of lipids in gut epithelial tissue. BACKGROUND OF THE INVENTION [0003] Pathological conditions that affect storage, breakdown and intestinal absorption of lipids are included in a broad category of so-called “lipid metabolism disorders,” and there are a variety of disorders that ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61P3/00C07K16/18
CPCA61K38/1709A61K2039/505Y10S977/80Y10S977/801C07K16/18A61P3/00A61P3/02A61P3/04A61P3/06A61P43/00A61P9/10
Inventor BURKLY, LINDAWANG, LI
Owner CURIS INC
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