Optimized miRNA constructs

• US 9,290,759 B2
• Filed: 08/25/2011
• Issued: 03/22/2016
• Est. Priority Date: 08/25/2010
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Abeliovich, Asa, Rhinn, Herv, Yamashita, Toru
• Primary Examiner(s): SCHNIZER, RICHARD A
• Application Number:
  US13/818,956
• Publication Number:
  US 20140051748A1
• Time in Patent Office: 1,671 Days
• Field of Search: None
• US Class Current: 1/1
• 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 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2330/00 Production

Abstract

The invention provides optimized miRNA sequences and their therapeutic use. The invention provides optimized miRNA constructs for treatment of neurodegenerative diseases.

Claims

1. An engineered mammalian pre-microRNA comprising SEQ ID NO:

6, 8, 12, 14, 16, 18, 24, 26, 33, 34, 40, 42, 48, or 50.

2. A therapeutic composition for intracerebral delivery comprising a pre-microRNA comprising SEQ ID NOs:

6, 8, 12, 14, 16, 18, 24, 26, 33, 34, 40, 42, 48, or 50, or any combination thereof.

3. A method to reduce aSyn levels in a cell or in a subject in need thereof comprising administering to a cell or a subject in need thereof a therapeutic amount of a pre-micro RNA smiR-7-2(SNCA) comprising SEQ ID NO:

40 or 42, a pre-micro RNA smiR-153-1(SNCA) comprising SEQ ID NO;

6 or 8, a pre-micro RNA smiR-495(SNCA) comprising SEQ ID NO;

48 or 50, or any combination thereof.

4. A method to treat Parkinson'"'"'s Disease in a subject in need thereof comprising administering to a subject in need thereof a therapeutic amount of a pre-micro RNA smiR-7-2(SNCA) comprising SEQ ID NO:

40 or 42, a pre-micro RNA smiR-153-1(SNCA) comprising SEQ ID NO;

6 or 8, a pre-micro RNA smiR-495(SNCA) comprising SEQ ID NO;

48 or 50, or any combination thereof.

5. A method to rescue or increase survival of dopaminergic neurons in a subject in need thereof comprising administering to a subject in need thereof a therapeutic amount of a pre-micro RNA smiR-7-2(SNCA) comprising SEQ ID NO:

40 or 42, a pre-micro RNA smiR-153-1(SNCA) comprising SEQ ID NO;

6 or 8, a pre-micro RNA smiR-495(SNCA) comprising SEQ ID NO;

48 or 50, or any combination thereof.

6. A method to rescue or increase survival of a dopaminergic neuron comprising contacting the neuron with a therapeutic amount of a pre-micro RNA smiR-7-2(SNCA) comprising SEQ ID NO:

40 or 42, a pre-micro RNA smiR-153-1(SNCA) comprising SEQ ID NO;

6 or 8, a pre-micro RNA smiR-495(SNCA) comprising SEQ ID NO;

48 or 50, or any combination thereof.

7. A method to reduce APP levels in a cell or in a subject in need thereof comprising administering to a cell or a subject in need thereof a therapeutic amount of a pre-micro RNA smiR-106(a)(APP) comprising SEQ ID NO:

26, a pre-micro RNA smiR-153(APP) comprising SEQ ID NO;

18, a smiR-101-1(APP) comprising SEQ ID NO;

14, or any combination thereof.

8. A method to treat Alzheimer'"'"'s disease in a subject in need thereof comprising administering to a subject in need thereof a therapeutic amount of a pre-micro RNA smiR-106(a)(APP) comprising SEQ ID NO:

26, a pre-micro RNA smiR-153(APP) comprising SEQ ID NO;

18, a smiR-101-1(APP) comprising SEQ ID NO;

14, or any combination thereof.