Use of rank/rankl antagonists for treating neuromuscular disorders, genetic myopathies and/or non genetic myopathies and/or for regulating skeletal and cardiac muscle disuse, diseases and aging

Abstract

The present invention relates to uses and methods comprising one or more RANK/RANKL antagonists or of a pharmaceutical composition comprising one or more RANK/RANKL antagonists and a pharmaceutically acceptable carrier for treating neuromuscular disorders, non-genetic myopathies, or genetic myopathies; maintaining and/or preserving the excitation:contraction:relaxation coupling; reducing loss of muscle strength associated with neuromuscular disorders, non-genetic myopathies or genetic myopathies; reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or regulating skeletal or cardiac muscle disuse, diseases and/or aging in a patient in need thereof. The present invention also relates to combinations and compositions comprising one or more RANK/RANKL antagonists and to methods for identifying candidate compounds.

1 .- 32 . (canceled) 
     
     
         33 . A method for:
 treating a neuromuscular disorder, a non-genetic myopathy, or a genetic myopathy;   reducing loss of muscle strength associated with the neuromuscular disorder, non-genetic myopathy or genetic myopathy;   reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or   regulating skeletal or cardiac muscle disuse, diseases and/or aging;   comprising administering one or more RANKL antagonists or a pharmaceutical composition comprising administering one or more receptor activators of nuclear factor kappa-B ligand (RANKL) antagonists or a pharmaceutical composition comprising a therapeutically effective amount of one or more RANKL antagonists and a pharmaceutically acceptable carrier to a patient in need thereof, wherein the antagonists inhibit RANKL activity in the patient, and wherein RANKL is a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 1.   
     
     
         34 . The method according to  claim 33 , wherein the neuromuscular disorder and/or genetic myopathy is Duchenne muscular dystrophy, Berker muscular dystrophy, a channelopathy, a muscle disease, Brody disease (SERCA1), amyotrophic lateral sclerosis, malignant hyperthermia, myopathy, muscle pain and rhabdomyolysis associated with drugs, muscle dysfunction and fatigue associated with aging, muscle dysfunction and weakness following renal failure, muscle dysfunction and weakness following heart failure, muscle dysfunction associated with diabetes, muscle dysfunction and weakness following chronic obstructive pulmonary disease (COPD), muscle atrophy and dysfunction following AIDS, muscle dysfunction following sepsis (septicemia), muscle weakness, atrophy and fatigue associated with Cushing's syndrome or prolonged administration of glucocorticoid drugs, muscle dysfunction following cast immobilization and prolonged bed rest and denervation, muscle dysfunction and cachexia associated with cancer, muscle dysfunction following ischemia/reperfusion, muscle dysfunctions following prolonged muscular activity, myositis ossificans, muscle damage following eccentric contraction as well as cardiac diseases and dysfunction. 
     
     
         35 . The method according to  claim 34 , wherein the muscle disease is a congenital myopathy, a central core disease or a multicore disease. 
     
     
         36 . The method according to  claim 34 , wherein said rhabdomyolysis associated with drugs is related to lipid lowering drugs named statin or rapamycin and FK506. 
     
     
         37 . The method according to  claim 34 , wherein said prolonged administration of glucocorticoid drugs is in connection with asthma, rheumatoid arthritis or another inflammatory disease. 
     
     
         38 . The method according to  claim 34  wherein said muscle dysfunctions following prolonged muscular activity is following running a marathon. 
     
     
         39 . The method according to  claim 33 , wherein:
 the RANKL antagonist is an OPG (osteoprotegerin) variant or an anti RANKL antibody;   the RANKL antagonist is a monoclonal anti-RANKL antibody; or   the RANKL antagonist is small interfering RNA, a microRNA, a precursor molecule, a ribozyme, an antisense, or an aptamer targeting RANKL.   
     
     
         40 . The method according to  claim 33 , wherein the RANKL antagonist is a humanized monoclonal anti-RANKL antibody, OPG, a microRNA, a precursor molecule, a ribozyme, an antisense, or an aptamer targeting RANKL. 
     
     
         41 . The method according to  claim 33 , wherein the RANKL antagonist is Denosumab. 
     
     
         42 . The method according to  claim 33 , further comprising administering one or more further therapeutic agents indicated for the treatment of neuromuscular disorders and genetic myopathies. 
     
     
         43 . The method according to  claim 42 , wherein the further therapeutic agent is one or more of:
 an angiotensin converting enzyme (ACE) inhibitor;   a sulfhydryl-containing agent;   a dicarboxylate-containing agent;   a Phosphonate-containing agent;   a hormonal therapy; a glucocorticoid;   a β2 agonist;   a proteolytic inhibitor for calpain;   a lysosomal enzyme and ubiquitin-proteasome system;   an antimyostatin therapy; or   a nutritional supplement therapy.   
     
     
         44 . The method according to  claim 43 , wherein the sulfhydryl-containing agent is Captopril or Zofenopril. 
     
     
         45 . The method according to  claim 43 , wherein the dicarboxylate-containing agent is Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril or Trandolapril. 
     
     
         46 . The method according to  claim 43 , wherein the phosphonate-containing agent is Fosinopril. 
     
     
         47 . The method according to  claim 43 , wherein the hormonal therapy comprises treatment with testosterone, growth hormones, or insulin growth factor. 
     
     
         48 . The method according to  claim 43 , wherein the glucocorticoid is prednisolone, prednosol or deflazacort. 
     
     
         49 . The method according to  claim 43 , wherein the β2 agonist is clambuterol or formoterol. 
     
     
         50 . The method according to  claim 43 , wherein the nutritional supplement therapy comprises treating with vitamin D, proteins, branched chain amino acids. 
     
     
         51 . The method of  claim 42 , wherein said one or more RANKL antagonists or said pharmaceutical composition and said one or more further therapeutic agents are administered simultaneous or consecutively. 
     
     
         52 . A method for identifying a candidate compound useful for:
 treating neuromuscular disorders, non-genetic myopathies, or genetic myopathies;   maintaining and/or preserving the excitation:contraction:relaxation coupling;   reducing loss of muscle strength associated with neuromuscular disorders, non-genetic myopathies or genetic myopathies;   reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or   regulating skeletal or cardiac muscle disuse, diseases and/or aging;   the method comprising the steps of:   a) contacting the candidate compound with a biological system comprising a RANK polypeptide or fragment thereof or a RANKL polypeptide or fragment thereof,   b) measuring the ability of the candidate compound to bind to the RANK polypeptide or fragment thereof or to the RANKL polypeptide, and   c) determining if the candidate compound is useful for:   treating neuromuscular disorders, non-genetic myopathies, or genetic myopathies;   maintaining and/or preserving the excitation:contraction:relaxation coupling;   reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or   regulating skeletal or cardiac muscle disuse, diseases and/or aging; based on the result of step b).   
     
     
         53 . A method for identifying a candidate compound useful for:
 treating neuromuscular disorders, non-genetic myopathies, or genetic myopathies;   maintaining and/or preserving the excitation:contraction:relaxation coupling;   reducing loss of muscle strength associated with neuromuscular disorders, non-genetic myopathies or genetic myopathies;   reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or   regulating skeletal or cardiac muscle disuse, diseases and/or aging;   the method comprising the steps of:   a) contacting the candidate compound with a biological system comprising a RANK polypeptide or fragment thereof or a RANKL polypeptide,   b) measuring the ability of the candidate compound to reduce or inhibit the interaction between the RANK polypeptide or fragment thereof or the RANKL polypeptide, and   c) determining if the candidate compound is useful for:   treating neuromuscular disorders, non-genetic myopathies, or genetic myopathies;   maintaining and/or preserving the excitation:contraction:relaxation coupling;   reducing loss of muscle strength associated with neuromuscular disorders, non-genetic myopathies or genetic myopathies;   reducing the loss of muscular strength associated with skeletal or cardiac muscle disuse, diseases and aging; or   regulating skeletal or cardiac muscle disuse, diseases and/or aging; based on the result of step b).   
     
     
         54 . The method of  claim 52 , wherein the measuring step comprises an ELISA assay, immunoprecipitation assay, coimmunoprecipitation assay, Western Blot assay, immunostaining assay or radioimmunoassay.