PHOSPHORODIAMIDATE MORPHOLINO OLIGOMERS (PMOS) AND THEIR USE IN SUPPRESSION OF MUTANT HUNTINGTIN EXPRESSION AND ATTENUATION OF NEUROTOXICITY

• US 20160017327A1
• Filed: 07/06/2015
• Published: 01/21/2016
• Est. Priority Date: 07/11/2014
• Status: Abandoned Application

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Rudnicki, Dobrila D., Margolis, Russell L.
• Application Number:
  US14/791,510
• Publication Number:
  US 20160017327A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses

Abstract

The present invention provides antisense phosphorodiamidate morpholino oligomers which are useful for the suppression or inhibition of the HTT gene involved in Huntington'"'"'s disease. The oligomers can selectively suppress mutant forms of the HTT protein while allowing the normal protein to be expressed in sufficient quantity to retain its function in the cell. Methods for treatment of Huntington'"'"'s disease are also provided.

Claims

1. An antisense phosphorodiamidate morpholino oligomer having the formula:

5′

-(CTG)_nC-3′

 

 

(I),

wherein n=5 to 15 trinucleotide repeats.

2. The oligomer of claim 1, wherein n=7 to 9.

3. The oligomer of claim 1, wherein the antisense phosphorodiamidate morpholino oligomer is selected from the group consisting of:

8. A composition comprising at least one or more oligomers of claim 1.

9. A pharmaceutical composition comprising at least one or more oligomers of claim 1 and a pharmaceutically acceptable carrier.

10. The composition of claim 8, further comprising at least one additional biologically active agent.

11. A method for reducing or inhibiting expression of HTT protein in a cell comprising contacting the cell with at least one or more oligomers of claim 1.

12. A method for reducing or inhibiting expression of HTT protein in a subject comprising administering to the subject an effective amount of the composition of claim 9.

13. The method of claim 12, wherein the oligomer is CTG28.

14. A method for treatment of Huntington'"'"'s Disease in a subject comprising administering to the subject an effective amount of the composition of claim 9.

4. An antisense phosphorodiamidate morpholino oligomer having a polynucleotide sequence of between 20 to 30 nucleotides in length, which is complimentary to the nucleotides immediately 3′

to the start codon of the HTT gene mRNA.

5. The oligomer of claim 4, having the sequence:

6. An antisense phosphorodiamidate morpholino oligomer having a polynucleotide sequence of between 20 to 30 nucleotides in length, which is complimentary to the nucleotides immediately 5′

from the start of the CAG repeat region of the HTT gene mRNA.

7. The oligomer of claim 6, having the sequence: