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Methods of enhancing lysosomal storage disease therapy by modulation of cell surface receptor density

a cell surface receptor and lysosomal storage technology, applied in the direction of peptide/protein ingredients, elcosanoid active ingredients, drug compositions, etc., can solve the problem of rapid removal of infused lysosomal enzymes from the blood, increase the uptake of extracellular lysosomal enzymes by cells, and increase the uptake of acid alpha glucosidase by the target organ

Inactive Publication Date: 2010-06-10
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method of increasing the uptake of lysosomal enzymes by up-regulating the cell surface density of carbohydrate-binding receptors on the surface of target cells. This is achieved by administering a pharmaceutical agent that selectively modulates the receptors. The method can be used to treat lysosomal storage diseases by increasing the uptake of the enzyme needed for treatment while avoiding the need for insulin treatment. The pharmaceutical agent can be insulin, glucose, protein kinase C activator, insulin-like growth factor, or other small molecule anti-diabetic drugs. The invention also relates to a method of selectively up-regulating M6P / IGF-II receptors on the surface of muscle cells for the treatment of Fabry disease.

Problems solved by technology

One of the major issues with ERT treatment for lysosomal storage diseases is that the infused lysosomal enzymes are rapidly removed from the blood stream by the liver, either through carbohydrate-binding receptors or non-specifically.

Method used

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  • Methods of enhancing lysosomal storage disease therapy by modulation of cell surface receptor density
  • Methods of enhancing lysosomal storage disease therapy by modulation of cell surface receptor density
  • Methods of enhancing lysosomal storage disease therapy by modulation of cell surface receptor density

Examples

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example 1

Dexamethasone Increases Uptake of Cerezyme® Enzyme by Liver Macrophage Cells in Vitro

[0084]Three representative cell types of the liver were assayed for CEREZYME® enzyme uptake under the influence of dexamethasone. An alveolar macrophage cell line was used to represent liver Kupffer cells, Hep3B cells were used to represent hepatocytes and liver sinusoidal endothelial cells (LSECs) were primary cells derived from the human liver.

[0085]The rat alveolar macrophage cell line NR 8383 (ATCC# CRL-2192) were cultured in Kaighn's modified F12K nutrient mixture (Gibco# 21127-002) with 2 mM L-glutamine (Gibco# 25030-081), 15% heat-inactivated fetal bovine serum (FBS) (Gibco# 16000-044) and 1× penicillin / streptomycin. Most of the cells were attached to the dish, with some in suspension. Hep3B cells were grown in MEM-eagle (Gibco# 11960-044) with Earles salts and 10% FBS, 1× non-essential amino acid (NEAA), 1× sodium pyruvate and 1× penicillin / streptomycin. Human liver sinusoidal endothelial c...

example 2

Dexamethasone Pretreatment Increases Uptake of Cerezyme® Enzyme by Tissue Macrophage Cells in Vivo

[0093]To assess the effect of dexamethasone treatment on CEREZYME® enzyme uptake by liver macrophage (Kupffer cells) in vivo, Fisher rats (female, ˜130 g) were divided into four groups (n=3). The first and second groups of rats only received vehicle PBS without dexamethasone, and the third and fourth groups were treated with water-soluble dexamethasone sodium phosphate (American Reagent Laboratories Inc.) at 10 μg and 100 μg (diluted into 200 l PBS) per rat through intraperitoneal injection. Four doses of dexamethasone were given over two consecutive days, one dose in early morning and one dose in late afternoon on each day. On the third day, CEREZYME® enzyme at 2.5 U per rat (˜18 U / kg) diluted in PBS was administrated into the second, third and fourth groups of rats through tail vein bolus injection. The first group was used as negative control.

[0094]Two hours after CEREZYME® enzyme i...

example 3

Insulin / Glucose Increases Alpha-Galactosidase Uptake by Cells in Vitro

[0101]Muscles are the major target tissues for enzyme replacement therapy of Pompe disease due to the lack of acid alpha-glucosidase. To determine if the M6P / IGF-II receptor-mediated lysosomal enzyme uptake pathway can be augmented by insulin / glucose, the effects of insulin / glucose were analyzed on induced muscle cells (myotubes) in vitro. L6 myoblasts (or induced myotubes) and Hep3B cells were cultured in 6-well dishes. Rat L6 myoblasts (ATCC# CRL-1458) were cultured at 37° C. under 5% CO2 in VitaCell DMEM media (ATCC# 30-2002) with 4 mM L-glutamine, 10% fetal bovine serum (Gibco #16000-044) and lx penicillin / streptomycin. Once confluent, cells were switched to VitaCell DMEM plus 2% horse sera (Gibco# 26050-088) and 1× penicillin / streptomycin. Media were changed every 3 days and at day 9-10, myotubes could be observed as multinuclear tubes. About 30-40% of the myoblasts formed myotubes. Cells were used for upta...

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Abstract

Methods of modulating uptake of extracellular lysosomal enzymes by administering a pharmaceutical agent and methods of treating a lysosomal storage disease (such as Gaucher disease, Pompe disease, Fabry disease or Niemann-Pick disease) or enhancing enzyme replacement therapy or gene therapy, comprising administering a pharmaceutical agent such as dexamethasone, glucose or insulin, are provided.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 408,670, filed Apr. 4, 2003, which claims the benefit of U.S. Provisional Application No. 60 / 370,747, filed Apr. 5, 2002. The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Lysosomal storage diseases are a group of rare genetic disorders comprising more than forty individual diseases. Currently, a promising treatment for these diseases is enzyme replacement therapy (ERT). Gene therapy, which employs a depot expression strategy where high-level expression of lysosomal enzymes in one organ can be secreted into the blood stream and carried to other organs for uptake, is another promising option. One of the major issues with ERT treatment for lysosomal storage diseases is that the infused lysosomal enzymes are rapidly removed from the blood stream by the liver, either through carbohydrate-binding receptors or non-specifically. For...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/47A61K38/28A61K31/7004A61K38/18A61K31/56A61K31/5575A61K38/20A61P43/00A61K31/557A61K31/565A61K31/573A61K31/715A61K38/19A61K38/30A61K45/06A61K45/08
CPCA61K31/557A61K31/565A61K31/573A61K31/715A61K38/28A61K38/465A61K48/00A61K38/47A61K45/06A61K2300/00A61P43/00
Inventor ZHU, YUNXIANGCHENG, SENG H.
Owner GENZYME CORP
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