Methods and compositions for treating neurological disease

• US 9,914,924 B2
• Filed: 01/05/2015
• Issued: 03/13/2018
• Est. Priority Date: 08/18/2005
• Status: Active Grant

• Current Assignee: University Of Massachusetts
• Original Assignee: University Of Massachusetts
• Inventors: Aronin, Neil, Zamore, Phillip
• Primary Examiner(s): Whiteman, Brian A
• Application Number:
  US14/589,807
• Publication Number:
  US 20150232840A1
• Time in Patent Office: 1,163 Days
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/178 miRNA, siRNA or ncRNA

Abstract

This invention relates to methods and compositions for treating neurological disease, and more particularly to methods of delivering iRNA agents to neural cells for the treatment of neurological diseases.

Claims

1. An isolated iRNA agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form an RNA duplex, wherein the antisense strand comprises a nucleotide sequence that differs by no more than four nucleotides from an antisense sequence of SEQ ID NO:

12, wherein the iRNA agent is conjugated to a cholesterol moiety, and wherein the iRNA agent further comprises a phosphorothioate or a 2′

-OMe modification.

2. The iRNA agent of claim 1, wherein the sense strand comprises a sequence of SEQ ID NO:

11.

3. The isolated iRNA agent of claim 1, wherein the cholesterol is conjugated to the sense strand.

4. The isolated iRNA agent of claim 3, wherein the cholesterol is conjugated to the 3′

end of the sense strand.

5. The isolated iRNA agent of claim 1, which is at least 21 nucleotides in length.

6. The isolated iRNA agent of claim 1, wherein the duplex region of the iRNA agent is about 18-25 nucleotides in length.

7. The isolated iRNA agent of claim 1, wherein the iRNA agent comprises a nucleotide overhang having 1 to 4 unpaired nucleotides.

8. A pharmaceutical composition, comprising:

(i) the isolated iRNA agent of claim 1; and

(ii) a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, comprising the sense strand of the iRNA agent comprises a sequence of SEQ ID NO:

11.

10. A method of downregulating expression of huntingtin (htt) mRNA in a neural cell distal to the site of administration, the method comprising contacting the iRNA agent of claim 1 with the neural cell for a time sufficient to allow uptake of the iRNA agent into the cell.

11. The method of claim 10, wherein the cell is contacted for a time sufficient to allow axonal transport of said iRNA.

12. The method of claim 10, wherein the iRNA agent is provided in a solution comprising a transfection reagent.

13. The method of claim 10 for treating a human further comprising identifying a human having Huntington'"'"'s disease, and administering to the human the iRNA agent.

14. The method of claim 13, wherein the iRNA agent comprises a nucleotide overhang having 1 to 4 unpaired nucleotides.

15. The method of claim 13, wherein the iRNA agent is administered as a sustained dose formulation, administered in multiple doses over a prolonged time period, or as a single dose.

16. The method of claim 13, comprising the administration of a second iRNA agent, wherein (i) the second iRNA agent comprises a sense and an antisense strand that form an RNA duplex, and (ii) the antisense strand of the iRNA agent comprises a nucleotide sequence sufficiently complementary to a second target sequence of about 18 to 25 nucleotides of the mRNA expressed from the htt gene.

17. The method of claim 10, wherein the neural cell is present in a subject and/or wherein the amount of huntingtin (htt) mRNA in the subject is reduced.

18. The method of claim 17, wherein the cells are contacted for a time sufficient to allow axonal transport of said iRNA.

19. A method of downregulating expression of htt mRNA in a neural cell, the method comprising contacting the iRNA agent of claim 1 with the neural cell for a time sufficient to allow uptake of the iRNA agent into the cell.

20. The method of claim 19 for treating a human further comprising identifying a human having Huntington'"'"'s disease, and administering to the human the iRNA agent.