RNAi Induced Huntingtin Gene Suppression

Patent metadata

Field	Value
Publication number	US-2020339992-A1
Application number	US-202016930035-A
Country	US
Kind code	A1
Filing date	Jul 15, 2020
Priority date	Dec 24, 2014
Publication date	Oct 29, 2020
Grant date	—

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.

First claim

1 . A method of reducing or delaying symptoms of Huntington's disease in a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, the method comprising administering to the subject 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 has a sequence length of at least 19 nucleotides and is complementary to SEQ ID NO:1.

2 . The method of claim 1 , wherein the Huntingtin allele comprises more than 35 CAG repeats.

3 . The method of claim 1 , wherein the Huntingtin allele comprises more than 39 CAG repeats.

4 . The method of claim 1 , wherein the viral vector is an adeno associated viral (AAV) vector.

5 . The method of claim 1 , wherein the AAV vector is a serotype 5 vector.

6 . 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.

7 . The method of claim 1 , wherein the viral vector is administered directly into the central nervous system (CNS).

8 . The method of claim 7 , wherein administration in the CNS comprises intrathecal infusion or injection into the striatum or thalamus.

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

10 . The method of claim 9 , wherein the expression cassette comprises a neuron-specific promoter selected from the group consisting of Neuron-Specific Enolase (NSE), human synapsin 1, caMK kinase, and tubuline.

11 . The method of claim 9 , wherein the viral vector is an AAV serotype 5 vector and the first strand of the double stranded RNA is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7.

12 . A method of treating a human subject carrying at least one Huntingtin allele with an abnormal number of CAG repeats, comprising administering to the subject 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 has a sequence length of at least 19 nucleotides and is complementary to SEQ ID NO:1.

13 . The method of claim 12 , wherein the Huntingtin allele comprises more than 35 CAG repeats.

14 . The method of claim 12 , wherein the Huntingtin allele comprises more than 39 CAG repeats.

15 . The method of claim 12 , wherein the viral vector is an adeno associated viral (AAV) vector.

16 . The method of claim 12 , wherein the AAV vector is a serotype 5 vector.

17 . The method of claim 12 , wherein the double stranded RNA is comprised in a pre-miRNA scaffold, a pri-miRNA scaffold, a shRNA, or an siRNA.

18 . The method of claim 12 , wherein the viral vector is administered directly into the central nervous system (CNS).

19 . The method of claim 18 , wherein administration in the CNS comprises intrathecal infusion or injection into the striatum or thalamus.

20 . The method of claim 12 , wherein the double stranded RNA is encoded by an expression cassette in the viral vector.

21 . The method of claim 20 , wherein the expression cassette comprises a neuron-specific promoter selected from the group consisting of Neuron-Specific Enolase (NSE), human synapsin 1, caMK kinase, and tubuline.

22 . The method of claim 21 , wherein the viral vector is an AAV serotype 5 vector and the first strand of the double stranded RNA is selected from the group consisting of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7.

Assignees

• Uniqure Ip Bv

Inventors

• Konstantinova Pavlina Stefanova
• MINIARIKOVÁ Jana

Classifications

• C12N2330/51

  Specially adapted vectors · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2310/531

  Stem-loop; Hairpin · CPC title

• C12N2310/3519

  Fusion with another nucleic acid · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title