G-rich polynucleotides as a novel therapeutic for the treatment of huntington's disease

Abstract

The present invention relates to oligonucleotide compositions and therapeutic uses thereof to modify protein-protein interactions. In particular, the invention relates to the use of a guanidine-rich oligonucleotides to disrupt disease-causing protein aggregates, for example, Huntington's Disease (HD) protein aggregates

1 . A method of inhibiting or reducing the formation of a protein aggregate comprising: providing an aptameric oligonucleotide having from 15 to 50 nucleotides, wherein at least 90% of the nucleotides are selected from the group consisting of guanosine, and thymidine nucleotides; and administering an effective amount of the oligonucleotide to a subject, wherein the oligonucleotide inhibits the gene expression of the aggregate-forming protein.  
     
     
         2 . The method of  claim 1 , wherein the aptameric oligonucleotide comprises from 18 to 24 nucleotides, and wherein at least 95% of the nucleotides are guanosine nucleotides.  
     
     
         3 . The method of  claim 1 , wherein the aptameric oligonucleotide forms a G-quartet structure and is capable of inhibiting the aggregation of huntingtin protein (Htt).  
     
     
         4 . The method of  claim 3 , wherein the aptameric oligonucleotide comprises the nucleotide sequence of SEQ ID NO. 3.  
     
     
         5 . The method of  claim 1 , wherein the aptameric oligonucleotide comprises the nucleotide sequence of SEQ ID NO. 10.  
     
     
         6 . A method of treating or preventing a disease in an individual related to the formation of a protein aggregate comprising the steps of: providing an aptameric oligonucleotide having from 15 to 50 nucleotides, wherein at least 90% of the nucleotides are selected from the group consisting of guanosine, and thymidine nucleotides; and administering an effective amount of the oligonucleotide in combination with at least one of a pharmaceutically acceptable carrier, excipient or both to a subject, wherein the oligonucleotide inhibits the gene expression of the aggregate-forming protein.  
     
     
         7 . The method of  claim 6 , wherein the disease is at least one member selected from the group consisting of Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, a prion disease, and a polyglutamine disease.  
     
     
         8 . The method of  claim 6 , wherein the aptameric oligonucleotide comprises from 18 to 24 nucleotides, and wherein at least 95% of the nucleotides are guanosine nucleotides.  
     
     
         9 . The method of  claim 8 , wherein the aptameric oligonucleotide forms a G-quartet structure and is capable of inhibiting the aggregation of huntingtin protein (Htt).  
     
     
         10 . The method of  claim 9 , wherein the aptameric oligonucleotide comprises the nucleotide sequence of SEQ ID NO. 3.  
     
     
         11 . The method of  claim 6 , wherein the aptameric oligonucleotide comprises the nucleotide sequence of SEQ ID NO. 10.  
     
     
         12 . A method of inhibiting the expression of Htt in a cell comprising: administering an effective amount of at least one aptameric oligonucleotide selected from the group consisting of SEQ ID NO. 3, and SEQ ID NO. 10, wherein the aptameric oligonucleotide specifically inhibits the expression of the Htt gene.