Modulation of micrornas against myotonic dystrophy type 1 and antagonists of micrornas therefor

Abstract

Modulation of microRNAs against myotonic dystrophy type 1 and antagonists of microRNAs therefor. The invention provides the use of inhibitors of microRNAs repressors of MBNL1 and/or MBNL2 genes for the manufacture of a medicinal product for the treatment of myotonic dystrophy 1. Inhibiting these microRNAs allows to increase the endogenous levels of the corresponding proteins MBNL1 and/or MBNL2, thereby alleviating symptoms of the disease, especially when inhibiting repressors that are expressed in the main affected organs: skeletal muscle, heart or organs of the central nervous system. The inhibition of the microRNAs miR-23b-3p and miR-218-5p is preferred. It also provides oligoribonucleotide or oligoribonucleotide analogue antagonists suitable therefor, preferably antagomiRs directed against the microRNAs mentioned with chemical modifications that enhance their interaction with the target, their stability in vivo and their ability to penetrate into the cells and distribute throughout tissues and organs.

1 - 28 . (canceled) 
     
     
         29 . An oligoribonucleotide analogue which is an antagonist of the human microRNA-218-5p or of the human microRNA-23b-3p , or a mixture of two or more of said oligoribonucleotide analogues, wherein said oligoribonucleotide analogue comprises a sequence of ribonucleotide and/or ribonucleotide analogue units having a sequence of nitrogenous bases that is at least 70% complementary to a sequence of nitrogenous bases of a fragment of the human microRNA-218-5p or of the human microRNA-23b-3p. 
     
     
         30 . The oligoribonucleotide analogue according to  claim 29 , comprising a fragment comprising a sequence of ribonucleotide and/or ribonucleotide analogues units having a sequence of nitrogenous bases that is 100% complementary to the sequence of the nitrogenous bases of the microRNA seed region of the human microRNA-218-5p or of the human microRNA-23b-3p. 
     
     
         31 . The oligoribonucleotide analogue according to  claim 29 , wherein the sequence of the nitrogenous bases of the ribonucleotide and/or ribonucleotide analogue units is identical in at least 70% to the sequence of the nitrogenous bases of the oligoribonucleotide SEQ ID NO: 1 or of the oligoribonucleotide SEQ ID NO: 2. 
     
     
         32 . The oligoribonucleotide analogue according to  claim 31 , wherein the sequence of the nitrogenous bases of the ribonucleotide and/or ribonucleotide analogue units is 100% identical to at least 15 consecutive nucleotides of the nitrogenous bases of the oligoribonucleotide SEQ ID NO: 1 or of the oligoribonucleotide SEQ ID NO: 2. 
     
     
         33 . The oligoribonucleotide analogue according to  claim 29 , wherein the oligoribonucleotide analogue is at least 15 nucleotides in length and is at least 70% complementary to SEQ ID NO: 3 or SEQ ID NO: 4. 
     
     
         34 . The oligoribonucleotide analogue according to  claim 29 , wherein the oligoribonucleotide analog is at least 15 nucleotides in length and is at least 93% complementary to SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         35 . The oligoribonucleotide analogue according to  claim 29 , which is an antagomiR, a blockmiR, an antimiR or a microRNA sponge. 
     
     
         36 . The oligoribonucleotide analogue according to  claim 29 , wherein the oligoribonucleotide analogue is at least 15 nucleotides in length and is identical in at least 70% to SEQ ID NO: 10 (antagomiR-218-5p) or SEQ ID NO: 11 (antagomiR-23b-3p). 
     
     
         37 . The oligoribonucleotide analogue according to  claim 36 , which is an antagomiR-type oligoribonucleotide analogue represented by SEQ ID NO: 10 (antagomiR-218-5p) or an antagomiR-type oligoribonucleotide analogue represented by SEQ ID NO: 11 (antagomiR-23b-3 p). 
     
     
         38 . The oligoribonucleotide analogue according to  claim 29 , which is an blockmiR-type selected by the group consisting of any of sequences SEQ ID NO: 84 to SEQ ID NO: 91, or which is an antimiR-type selected from the group consisting of any of sequences SEQ ID NO: 92 to SEQ ID NO: 94. 
     
     
         39 . A composition comprising at least one oligoribonucleotide analogue of  claim 29 , a mixture of two or more of said oligoribonucleotide analogues, or an expression vector that comprises at least one of said oligoribonucleotide analogues. 
     
     
         40 . The composition according to  claim 39 , further comprising a carrier and/or one or more pharmaceutically acceptable excipients. 
     
     
         41 . The composition according to  claim 39 , comprising an antagomiR-type oligoribonucleotide analogue represented by SEQ ID NO: 10 (antagomiR-218-5p) or an antagomiR-type oligoribonucleotide analogue represented by SEQ ID NO: 11 (antagomiR-23b-3p) or a mixture thereof.