# US 10,767,180 B2 · RNAi induced huntingtin gene suppression

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- Number: US 10,767,180 B2
- Document ID: US10767180B2
- Status: Granted
- Kind: B2
- Application number: 16/193,908
- Filed: 2018-11-16
- Published: 2019-05-16
- Granted: 2020-09-08
- Earliest claimed: 2014-12-24
- Assignees: uniQure IP B.V.
- Applicants: uniQure IP B.V.
- Inventors: Pavlina Stefanova Konstantinova; Jana Miniariková
- Web page: https://patentgrep.com/patent/US10767180B2

## CPC

- 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)}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/3519: Fusion with another nucleic acid
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2330/51: Specially adapted vectors
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides for a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence has a sequence length of at least 19 nucleotides and is substantially complementary to SEQ ID NO. 1. Said double stranded RNA is for use in inducing RNAi against Huntingtin exon 1 sequences. The double stranded RNA of to the invention was capable of reducing neuronal cell death and huntingtin aggregates in an animal model.

## Claims

### Claim 1

A method of reducing expression of an RNA transcript comprising SEQ ID NO:1 in a neuron, method comprising introducing into the neuron a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

### Claim 2 (depends on 1)

The method of claim 1, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA.

### Claim 3 (depends on 1)

The method of claim 1, wherein the first RNA sequence comprises 19-27 nucleotides.

### Claim 4 (depends on 1)

The method of claim 1, wherein the double stranded RNA is encoded by an expression cassette.

### Claim 5 (depends on 4)

The method of claim 4, wherein the expression cassette comprises a neuron-specific promoter.

### Claim 6 (depends on 1)

The method of claim 1, wherein the first strand and second strand are respectively selected from the group consisting of SEQ ID NOs: 3 and 8; SEQ ID NOs: 4 and 9; SEQ ID NOs: 5 and 10; SEQ ID NOs: 5 and 13; SEQ ID NOs: 5 and 14; SEQ ID NOs: 6 and 11; and SEQ ID NOs: and 7 and 12.

### Claim 7 (depends on 1)

The method of claim 1, wherein the double stranded RNA is comprised in a pre-miRNA scaffold derived from miR-451a or miR-155.

### Claim 8 (depends on 1)

The method of claim 1, wherein the double stranded RNA is introduced into the neuron through transduction by a viral vector.

### Claim 9 (depends on 8)

The method of claim 8, wherein the viral vector is an adeno associated viral (AAV) vector.

### Claim 10 (depends on 9)

The method of claim 9, wherein the AAV vector is a serotype 5 vector.

### Claim 11

A method of treating a subject with Huntington's disease or a subject that is genetically predisposed for Huntington's disease who does not yet show symptoms of Huntington's disease, comprising administering to a subject with Huntington's disease an effective amount of a viral vector encoding a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence comprises SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

### Claim 12 (depends on 11)

The method of claim 11, wherein the viral vector is an adeno associated viral (AAV) vector.

### Claim 13 (depends on 11)

The method of claim 11, wherein the AAV vector is a serotype 5 vector.

### Claim 14 (depends on 11)

The method of claim 11, wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA.

### Claim 15 (depends on 11)

The method of claim 11, wherein the viral vector is administered directly into the central nervous system (CNS).

### Claim 16 (depends on 15)

The method of claim 15, wherein administration in the CNS comprises intrathecal infusion or injection into at least one of the striatum and thalamus.

### Claim 17 (depends on 11)

The method of claim 11, wherein the double stranded RNA is encoded by an expression cassette in the viral vector.

### Claim 18 (depends on 17)

The method of claim 17, wherein the expression cassette comprises a neuron-specific promoter.