Prostaglandin e2 modulation and uses thereof

Abstract

Methods, uses, kits and products are described for the prognosis, diagnosis, prevention and treatment of myotronic dystrophy type 1 (DM1), and more particularly for the prognosis, diagnosis, prevention and treatment of the congenital form of myotronic dystrophy type 1 (cDM1), based on changes in/modulation of prostaglandin E 2 (PGE 2 ).

1 . A method for preventing and/or treating congenital myotonic dystrophy type 1 (cDM1) in a subject comprising inhibiting the biosynthesis or activity of prostaglandin E 2  (PGE 2 ) in said subject. 
     
     
         2 . The method of  claim 1 , wherein said inhibition is through the inhibition of the expression and/or activity of a mediator involved in PGE 2  biosynthesis. 
     
     
         3 . The method of  claim 1 , comprising the administration, to said subject, of a therapeutically-effective amount of an inhibitor of expression and/or activity of a mediator involved in PGE 2  biosynthesis. 
     
     
         4 . The method of  claim 3 , wherein said inhibitor is a nonsteroidal anti-inflammatory drug (NSAID) or a cyclooxygenase (COX) inhibitor. 
     
     
         5 . The method of  claim 4 , wherein said inhibitor is acetylsalicylic acid. 
     
     
         6 . The method of  claim 4 , wherein said NSAID is a COX-2 inhibitor. 
     
     
         7 . The method of  claim 2 , wherein said mediator involved in PGE 2  biosynthesis is an inducible enzyme involved in PGE 2  biosynthesis. 
     
     
         8 . The method of  claim 7 , wherein said mediator is microsomal PGE synthase-1 (mPGES-1). 
     
     
         9 . The method of  claim 8 , wherein said inhibition is with a short hairpin RNA (shRNA) or a small interfering RNA (siRNA). 
     
     
         10 . The method of  claim 9 , wherein said shRNA is encoded by a nucleic acid comprising the sequence of SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         11 . A method of prognosticating or diagnosing cDM1 in a first subject, said method comprising (a) comparing the level or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii) in a biological sample from said first subject with a corresponding reference level or activity; and (b) prognosticating or diagnosing cDM1 in accordance with said comparison. 
     
     
         12 . The method of  claim 11 , wherein said reference level or activity is the level or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii) in a corresponding biological sample from a second subject not suffering from cDM1, and wherein a higher level or activity in the sample from said first subject relative to the level in the sample from said second subject is indicative that said first subject has or is at risk of developing cDM1. 
     
     
         13 . The method of  claim 11 , wherein said reference level or activity is the level or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii) in a corresponding biological sample from a second subject suffering from cDM1, and wherein a substantially similar level or activity in the sample from said first subject relative to the level or activity in the sample from said second subject is indicative that said first subject has or is at risk of developing cDM1. 
     
     
         14 . The method of  claim 11 , wherein said biological sample is a muscle cell sample. 
     
     
         15 . The method of  claim 14 , wherein said muscle cell sample is a myoblast sample. 
     
     
         16 . The method of  claim 11 , wherein said mediator is COX-2. 
     
     
         17 . The method of  claim 16 , wherein said method comprises determining the level or activity of a polypeptide comprising residues 18-604 of the amino acid sequence of SEQ ID NO: 12. 
     
     
         18 . The method of  claim 16 , wherein said method comprises determining the level of a nucleic acid encoding a polypeptide comprising residues 18-604 of the amino acid sequence of SEQ ID NO: 12. 
     
     
         19 . The method of  claim 18 , wherein said nucleic acid comprises the nucleotide sequence of SEQ ID NO:11. 
     
     
         20 . A method for determining whether a test compound is useful for preventing and/or treating cDM1, said method comprising determining the level and/or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii), in a cell comprising (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii), and/or PGE 2  biosynthetic activity; wherein a decrease in the level and/or activity in the presence relative to the absence of said test compound is indicative that said test compound is useful for preventing and/or treating cDM1. 
     
     
         21 . A method for determining whether a test compound is useful for preventing and/or treating cDM1, said method comprising:
 (a) contacting a biological sample from a subject at risk of or suffering from cDM1 with said test compound; and   (b) determining the level and/or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii);   
       wherein a decrease in the level and/or activity in the presence relative to in the absence of said test compound is indicative that said test compound is useful for preventing and/or treating cDM1. 
     
     
         22 . A method for determining whether a test compound is useful for preventing and/or treating cDM1, said method comprising assaying the level and/or activity of (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii), in the presence versus in the absence of said test compound, wherein a decrease in the level and/or activity in the presence relative to the absence of said test compound is indicative that said test compound is useful for preventing and/or treating cDM1. 
     
     
         23 . The method of  claim 22 , wherein said assaying comprises contact said test compound with a cell comprising (i) PGE 2 , (ii) a mediator involved in PGE 2  biosynthesis, or (iii) both (i) and (ii). 
     
     
         24 . The method of  claim 22 , wherein said assaying comprises contact said test compound with a mediator involved in PGE 2  biosynthesis. 
     
     
         25 . The method of  claim 22 , wherein said mediator is COX-2 or mPGES-1. 
     
     
         26 . The method of  claim 21 , wherein said biological sample is a muscle cell sample or a muscle cell precursor sample. 
     
     
         27 . The method of  claim 26 , wherein said muscle cell precursor sample is a myoblast sample. 
     
     
         28 . The method of  claim 20 , further comprising:
 (d) contacting a myoblast sample from a subject at risk of or suffering from cDM1 with said test compound;   (e) culturing said myoblasts under conditions suitable for myoblast differentiation; and   (f) determining the level of differentiation of said myoblast;   
       wherein an increase in the level of differentiation of said myoblasts in the presence relative to the absence of said test compound is indicative that said test compound is useful for preventing and/or treating cDM1. 
     
     
         29 . The method of  claim 28 , wherein said level of differentiation is determined by measuring the index of fusion of said myoblasts after said culturing.