Methods and Compositions to Modulate RNA Processing

Abstract

The present disclosure provides methods and compositions to selectively modulate RNA processing. The methods and compositions selectively enhance or repress RNA processing by up- or down-regulating Drosha expression and/or by providing RNA sequences with mismatches introduced or removed 5 and/or 9-12 nucleotide positions from the Drosha cutting site. Therapeutic uses of the methods and compositions are also described.

What is claimed is: 
     
         1 . An expression vector encoding an endogenous RNA-based molecule altered to encode at least one mis-match at nucleotide position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         2 . An expression vector of  claim 1  altered to encode two mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         3 . An expression vector of  claim 1  altered to encode three mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         4 . An expression vector of  claim 1  altered to encode four mis-matches at nucleotide positions selected from 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         5 . An expression vector of  claim 1  altered to encode five mis-matches at nucleotide positions 5, 9, 10, 11 and 12 from the RNA's Drosha cutting site. 
     
     
         6 . An RNA-based molecule comprising an endogenous RNA sequence altered to include at least one mis-match at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         7 . An RNA-based molecule of  claim 6  altered to include at least two mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         8 . An RNA-based molecule of  claim 6  altered to include at least three mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         9 . An RNA-based molecule of  claim 6  altered to include at least four mis-matches at position 5, 9, 10, 11 or 12 from the RNA's Drosha cutting site. 
     
     
         10 . An RNA-based molecule of  claim 6  altered to include five mis-matches at position 5, 9, 10, 11 and 12 from the RNA's Drosha cutting site. 
     
     
         11 . An RNA-based molecule of  claim 6 , wherein the RNA is miRNA. 
     
     
         12 . A method of selectively targeting a tissue or cell type with high Drosha expression levels for up-regulation of an RNA molecule comprising administering an RNA-based molecule of  claim 6  to a subject. 
     
     
         13 . A method of  claim 12  wherein the selective targeting results in a higher level of the up-regulated RNA molecule in liver over brain; in intestine over liver and pancreas; in ovaries over uterus; malignant cells over non-malignant cells or in young T-cells over mature T-cells.