Inhibition of the expression of huntingtin gene

• US 7,589,189 B2
• Filed: 04/30/2004
• Issued: 09/15/2009
• Est. Priority Date: 05/14/2003
• Status: Expired due to Fees

• Current Assignee: Japan Science & Technology Trading Co. Limited
• Original Assignee: Japan Science & Technology Trading Co. Limited
• Inventors: Murata, Miho, Wada, Keiji, Wang, Yu-Lai, Wanzhao, Liu, Ichiro, Kanazawa, Goto, Jun
• Primary Examiner(s): McGarry; Sean
• Assistant Examiner(s): GIBBS, TERRA C
• Application Number:
  US10/556,711
• Publication Number:
  US 20080015158A1
• Time in Patent Office: 1,964 Days
• Field of Search: 536/23.1, 536/24.3, 536/24.33, 536/24.5, 514/44
• US Class Current: 536/24.5
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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.

Abstract

It is intended to provide methods for suppressing the huntington gene expression by using a double-stranded RNA (dsRNA), huntington gene expression inhibitors to suppress the huntington gene expression, and preventives and/or remedies of Huntington'"'"'s disease. Targeting against a specific sequence of mRNA at immediately upstream of CAG repeats in HD genes of Huntington'"'"'s disease, the huntington gene expression is suppressed by using a dsRNA homologous to the sequence. In this invention, a short siRNA (short double-stranded RNA) having bp as short as around 21-23 bp can be effectively used as the dsRNA homologous to a specific RNA sequence in a region at immediately upstream of CAG repeats. The dsRNA of this present invention can be used as a huntington gene expression inhibitor, or a preventive and/or a remedy of Huntington'"'"'s disease by administering or introducing into a living body or a living cell in mammals for the prevention and/or treatment of Huntington'"'"'s disease.

Claims

1. A double-stranded RNA which is composed of sense- and antisense-strand RNAs, fully homologous to the sequence composed of base sequences shown in SEQ. ID NOs:

3 and 4 in the sequence listing, wherein the double-stranded RNA can inhibit huntington gene expression.

2. The double-stranded RNA according to claim 1 prepared from synthesized sense- and antisense-strand RNAs.

3. The double-stranded RNA according to claim 1, which is prepared from sense- and antisense-strand RNAs generated by using gene recombination.

4. The double-stranded RNA according to claim 3, wherein the sense- and antisense-strand RNAs generated by using gene recombination are prepared by obtaining RNAs which are generated by introducing a expression vector incorporated DNA capable of transcribing respectively the RNAs, into a host cell.

5. A huntington gene expression inhibitor composed of the double-stranded RNA according to any one of claims 1, and 2 to 4.

6. A huntington gene expression inhibitor composed of a fusion product, wherein the double-stranded RNA according to any one of claims 1, and 2 to 4 is added to a TAT sequence, a protein transduction domain derived from HIV-1.

7. A huntington gene expression inhibitor composed of a complex formed from the double-stranded RNA according to any one of claims 1, and 2 to 4 and a positively-charged ribosome/lipid.

8. A huntington gene expression inhibitor composed of an expression vector incorporating a DNA capable of transcribing the double-stranded RNA according to claim 1.

9. A remedy of Huntington'"'"'s disease containing the huntington gene expression inhibitor according to claim 5 as an effective ingredient.

10. The remedy of Huntington'"'"'s disease according to claim 9 further containing a pharmaceutically acceptable carrier.