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Therapeutic and prophylactic methods for neuromuscular disorders

a neuromuscular disorder and prophylactic method technology, applied in the field of clinical pathophysiology, can solve the problems of abnormal sarcolemmal membrane tearing, no effective arresting of the disease course, and many forms of muscular dystrophies that are fatal and currently incurable, so as to reduce the prednisone-induced muscle atrophy and increase muscle mass and strength

Inactive Publication Date: 2010-12-23
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present invention is based, in part, on the discovery and demonstration that, in a mouse model of DMD, treatment by administration of a neutralizing anti-GDF-8 antibody and prednisone is more effective in increasing muscle mass and strength relative to treatment with prednisone alone. The invention is further based, in part, on the discovery and demonstration that administration of anti-GDF-8 antibody with prednisone reduces prednisone-induced muscle atrophy.

Problems solved by technology

Many forms of muscular dystrophies are fatal and currently incurable.
Alteration or absence of this protein results in abnormal sarcolemmal membrane tearing.
Many pharmacological agents have been tried in MD but none has proved effective in arresting the course of the disease.
However, corticosteroids administered over time can induce muscle atrophy, which primarily affects proximal muscles—the very same muscles that are affected in DMD and BMD.
The corticosteroid-induced muscle and other side effects may limit the long-term effectiveness of corticosteroid therapy.

Method used

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  • Therapeutic and prophylactic methods for neuromuscular disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of GDF-8 Neutralizing Antibody on Dystrophic Muscle

[0057]The ability of in vivo inhibition of GDF-8 to ameliorate muscular dystrophy was tested in the mdx mouse model of DMD. Five to seven week old male C57BL / 10ScSn-mdx / j mice (Jackson Laboratory, Bar Harbor, Me.) were treated with weekly intraperitoneal injections of the GDF-8 neutralizing murine antibody JA-16 (60 mg / kg, double dosing at first week, n=11), and vehicle alone (control group, n=10) for 12 weeks. These mice were also compared to mice of the same background strain (C57BL / 10, n=12) without the dystrophin deficiency.

[0058]The body weight was monitored before, during and after treatment. Mice in the treatment group gained weight relative to mice in the vehicle control group. Results are shown in Table 1.

TABLE 1Total body weight (g) Average values with SEMWeekJA-16vehicle controlvehicle controlof trial(mdx)(mdx)(non-mdx)021.92 + / − 0.4222.51 + / − 0.3619.18 + / − 0.40427.82 + / − 0.4326.76 + / − 0.6024.14 + / − 0.27829.59 + / − ...

example 2

Effect of GDF-8 Neutralizing Antibody and Prednisone on Normal and Dystrophic Muscle

[0061]Male C57BL / 10ScSn-mdx / j and C57BL / 10 (Jackson Laboratory, Bar Harbor, Me.). Mouse monoclonal anti-GDF-8 antibody JA-16, prednisone (P-9901, Sigma), or vehicle (peanut oil) was injected starting at age 5-7 weeks for 4 weeks. Mice were intraperitoneally (IP) injected with JA-16 at a dose of 60 mg / kg per week (double dosing at first week), or subcutaneously (SC) injected with prednisone at 2 mg / kg, 3 times a week.

[0062]The body weight and grip strength were monitored before, during and after treatment. Results are shown in Table 3 and Table 4, respectively.

TABLE 3Total body weight (average ± SEM, g)WeekPrednisone +vehiclevehicleofJA-16Prednisonecontrolcontroltrial(mdx)(mdx)(mdx)(non-mdx)017.7 ± 1.617.6 ± 1.816.0 ± 1.919.2 ± 0.4122.1 ± 1.420.9 ± 1.819.1 ± 2.122.4 ± 0.3225.9 ± 1.224.2 ± 1.623.7 ± 1.423.8 ± 0.4326.5 ± 1.124.7 ± 1.524.8 ± 1.224.9 ± 0.4428.1 ± 1.225.9 ± 1.625.7 ± 1.425.6 ± 0.5

TABLE 4Gr...

example 3

Effect of GDF-8 Neutralizing Antibody on Prednisone-Induced Muscle Atrophy

[0066]In the mice treated as described in Example 2, diaphragm muscle was histologically examined as described in Example 1. The morphological changes were evaluated by an independent pathology lab that had no knowledge of the treatment group assignments. Severity grades were assigned on a scale from 0 to 4 (0=none; 1=minimal; 2=mild; 3=moderate; and 4=marked). Results are shown in FIG. 1A (severity scores) and FIG. 1B (percentage of muscle fibers atrophied). The results show that administration of the anti-GDF-8 antibody with prednisone reduces prednisone-induced muscle atrophy.

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Abstract

The disclosure provides methods for treating neuromuscular disorders in mammals. The disclosed methods include administering therapeutically effective amounts of a GDF-8 inhibitor and a corticosteroid to a subject susceptible to, or having, a neuromuscular disorder, so as to maintain desirable levels of muscle function.

Description

[0001]This is a continuation of application Ser. No. 10 / 858,353, filed Jun. 1, 2004, which claims priority to U.S. provisional application No. 60 / 474,603, filed on Jun. 2, 2003, all of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to the field of clinical pathophysiology, and more particularly to methods for treating neuromuscular disorders, such as muscular dystrophies. The invention also relates to pharmaceutical formulations containing corticosteroids and inhibitors of growth and differentiation.BACKGROUND OF THE INVENTION[0003]Muscular dystrophies (MD) are progressive inherited neuromuscular disorders that are characterized by muscle wasting and weakness (Emery (2002) The Lancet, 359:687-695). Many forms of muscular dystrophies are fatal and currently incurable.[0004]Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular disease. The disease is caused by mutations in the DMD gene coding...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/56A61K31/573A61K38/22A61K38/02A61P21/00A61P25/00C07K16/24
CPCA61K39/39533A61K2039/505C07K16/24A61K2300/00A61P11/00A61P17/00A61P17/06A61P19/02A61P21/00A61P21/04A61P25/00A61P25/02A61P29/00A61P3/14A61P37/02A61P37/06A61P37/08A61P43/00A61P9/04A61K31/573C07K16/18A61K39/395
Inventor WHITTEMORE, LISA-ANNELI, XIANGPING
Owner WYETH LLC
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