Method relating to myostatin pathway inhibition

Abstract

The present invention provides a method for determining whether a patient will respond to treatment with a myostatin pathway inhibitor, the method comprising: (a) determining a level of myostatin and/or activin type II receptor (ActRII) and/or follistatin in at least one muscle biopsy obtained from a treatment target muscle in a subject having or suspected of having muscle atrophy or a muscle wasting condition; and (b) determining a level of myostatin and/or follistatin in a systemic sample obtained from the patient, wherein if: (i) the level of myostatin in the systemic sample is higher than a threshold and/or if the level of follistatin in the sample is lower than a threshold; and (ii) the level of myostatin and/or ActRII receptor in the at least one biopsy sample is higher than a threshold level and/or if the level of follistatin in the at least one biopsy sample is lower than a threshold level, the patient will respond to treatment.

We claim: 
     
         1 . A method for treating muscle atrophy or a muscle wasting condition to a subject in need thereof, the method comprising:
 administering a dystrophin, an MTM1 gene, or pathology correcting therapy, and a myostatin pathway inhibitor to the subject, thereby treating the muscle atrophy or the muscle wasting condition.   
     
     
         2 . The method according to  claim 1 , wherein the myostatin pathway inhibitor is a myostatin antagonist or an ActRII antagonist. 
     
     
         3 . The method according to  claim 2 , wherein the myostatin antagonist is an anti-myostatin antibody, a myostatin decoy, a follistatin, or a follistatin analogue. 
     
     
         4 . The method according to  claim 2 , where the ActRII antagonist is an anti-ActRII antibody, an ActRII decoy, or an inhibitor of an effector downstream of the ActRII. 
     
     
         5 . The method according to  claim 1 , wherein the muscle atrophy or muscle wasting condition is a muscle dystrophy such as: Becker Muscular Dystrophy (BMD), Duchenne Muscular Dystrophy (DMD), Facioscapulohumeral Dystrophy (FSHD), Limb Girdle Muscular Dystrophy (LGMD), or Congenital Muscular Dystrophy (CMD); a central or spinal muscular atrophy such as: Amyotrophic Lateral Sclerosis (ALS) or spinal muscular atrophy; a neurogenic muscular atrophy such as: Charcot-Marie-Tooth peripheral neuropathy; a congenital myopathy such as: Myotubular myopathy; or an ‘idiopathic’ muscle wasting condition such as: Inclusion Body Myositis (IBM) or age-related sarcopenia. 
     
     
         6 . The method according to  claim 1 , comprising administering to the subject a vector comprising the MTM1 gene. 
     
     
         7 . The method according to  claim 6 , wherein the viral vector is a retrovirus vector, an adenovirus vector, a lentivirus vector, a herpes simplex virus vector, or an adeno-associated virus vector. 
     
     
         8 . The method according to  claim 1 , wherein the MTM1 gene and myostatin pathway inhibitor are administered separately, simultaneously or sequentially. 
     
     
         9 . The method according to  claim 1 , wherein the MTM1 gene is administered prior to the myostatin pathway inhibitor. 
     
     
         10 . A method for improving or monitoring dystrophin or MTM1 gene or pathology correcting therapy, the method comprising determining a level of myostatin and/or ActRII and/or follistatin in a sample obtained from a subject. 
     
     
         11 . The method according to  claim 10 , wherein
 a) determining a level of myostatin and/or ActRII and/or follistatin comprises measuring myostatin and/or ActRII and/or follistatin protein; or   b) determining a level of myostatin and/or ActRII and/or follistatin comprises measuring myostatin and/or ActRII and/or follistatin mRNA.   
     
     
         12 . The method according to  claim 10 , wherein the myostatin is measured in a pro-peptide or mature protein form. 
     
     
         13 . The method according to  claim 10 , wherein
 a) the sample is a bodily fluid sample such as: a whole blood sample, a serum sample, a plasma sample or a urine sample; or   b) a biopsy sample such as: a muscle biopsy, including a skeletal muscle biopsy sample.   
     
     
         14 . The method according to  claim 10 , further comprising comparing the level of myostatin and/or follistatin to a threshold. 
     
     
         15 . The method according to  claim 14 , wherein if the level of myostatin is below the threshold and/or if the level of follistatin is above the threshold, at least one further round of gene or pathology correcting therapy is administered to the subject. 
     
     
         16 . A method for treating muscle atrophy or a muscle wasting condition, the method comprising administering a dystrophin, MTM1 gene, or pathology correcting therapy to a subject having a myostatin and/or ActRII level lower than a threshold level. 
     
     
         17 . The method according to  claim 16 , wherein the subject has at least one skeletal muscle that does not express ActRII. 
     
     
         18 . A method for determining anabolic capacity of the skeletal muscle system of a subject, the method comprising:
 (a) determining a level of myostatin and/or follistatin in a systemic sample obtained from the subject; and/or   (b) determining a level of myostatin and/or ActRII and/or follistatin in at least one muscle biopsy obtained from the subject; wherein if
 (i) the level of myostatin in the systemic sample is lower than a threshold and/or if the level of follistatin in the systemic sample is higher than a threshold; and/or 
 (ii) the level of myostatin and/or ActRII receptor in the at least one muscle biopsy sample is lower than a threshold level and/or if the level of follistatin in the at least one muscle biopsy sample is higher than a threshold level,
 the anabolic capacity of the skeletal muscle system is compromised, indicating the existence of a muscle wasting process in the subject. 
 
   
     
     
         19 . The method according to  claim 18 , further comprising comparing one or more of the levels of myostatin, ActRII receptor and/or follistatin to a respective threshold to determine the activity of the muscle wasting process. 
     
     
         20 . The method according to  claim 18 , further comprising treating the subject with a dystrophin, MTM1 gene or pathology correcting therapy, and/or a myostatin pathway inhibitor. 
     
     
         21 . A method for determining whether a patient having or suspected of having spinal muscular atrophy (SMA) will respond to treatment, the method comprising:
 determining a level of myostatin and/or follistatin and/or GDF11 in a systemic sample obtained from the patient;   wherein a level of GDF11 above a threshold is associated with SMA; and   wherein if the level of myostatin is higher than a threshold and/or if the level of follistatin in the sample is lower than a threshold,   the patient will respond to treatment.   
     
     
         22 . The method according to  claim 22 , wherein the systemic sample is a bodily fluid sample such as: a whole blood sample, a serum sample, a plasma sample or a urine sample. 
     
     
         23 . The method according to  claim 21 , further comprising administering a treatment for SMA to a patient determined to respond to the treatment.