Modulation of transthyretin expression

• US 8,101,743 B2
• Filed: 11/19/2008
• Issued: 01/24/2012
• Est. Priority Date: 04/05/2004
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Brown-Driver, Vickie L., Jain, Ravi
• Primary Examiner(s): SHIN, DANA H
• Application Number:
  US12/273,731
• Publication Number:
  US 20090082300A1
• Time in Patent Office: 1,161 Days
• Field of Search: 536/23.1, 536/24.5, 435/325, 435/375, 800/12
• US Class Current: 536/24.5
• 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 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• 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: Y10T 436/143333 Saccharide [e.g., DNA, etc.]

Abstract

Compounds, compositions and methods are provided for modulating the expression of transthyretin. The compositions comprise oligonucleotides, targeted to nucleic acid encoding transthyretin. Methods of using these compounds for modulation of transthyretin expression and for diagnosis and treatment of diseases and conditions associated with expression of transthyretin are provided.

Claims

1. A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides, wherein said modified oligonucleotide comprises a nucleobase sequence that is 100% complementary to SEQ ID NO:

4 as measured over the entirety of said modified oligonucleotide, wherein said nucleobase sequence has at least 95% identity to SEQ ID NO;

74, and wherein said modified oligonucleotide comprises;

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides; and

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

2. The compound of claim 1, wherein the modified sugar is a 2′

-O-methoxyethyl or a 4′

-(CH₂)_n-O-2′

bridge, wherein n is 1 or 2.

3. The compound of claim 1, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

4. The compound of claim 1, wherein the modified oligonucleotide comprises at least one 5-methylcytosine.

5. The compound of claim 1, wherein the modified sugar is a bicyclic sugar.

6. The compound of claim 1, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each of said nucleosides of each of the wing segments comprises a 2′

-O-methoxyethyl sugar, wherein each cytosine of said modified oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.

7. A composition comprising:

the compound of claim 1, or a salt thereof and, a pharmaceutically acceptable carrier or diluent.

9. The compound of claim 3, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

8. The compound of 1, wherein the modified sugar is a sugar mimetic.