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Modulation of transthyretin expression

a technology of transthyretin and expression, applied in the field of antisense compounds, can solve the problems of not being able to address conditions, not being able to suppress the variant transthyretin, and limited success of this therapy, and achieve the effect of modulating the expression of transthyretin

Inactive Publication Date: 2005-11-03
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] The present invention is directed to antisense compounds, especially nucleic acid and nucleic acid-like oligomers, which are targeted to a nucleic acid encoding transthyretin, and which modulate the expression of transthyretin. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of screening for modulators of transthyretin and methods of modulating the expression of transthyretin in cells, tissues or animals c

Problems solved by technology

The success of this therapy was limited, however, with gene conversion rates of 11% in vitro and 9% in vivo.
These levels are not sufficient for suppression of the variant transthyretin in clinical terms (Nakamura et al., Gene Ther, 2004).
However, this therapy is associated with several problems, and does not address conditions which are caused by transthyretin variant production in tissues other than liver (Yazaki et al., Muscle Nerve, 2003, 28, 438-442).

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Nucleoside Phosphoramidites

[0108] Synthesis of nucleoside phorsphoramidates, including amidites and their intermediates were prepared as described in U.S. Pat. No. 6,426,220 and published PCT WO 02 / 36743, both of which are incorporated herein by reference.

example 2

Oligonucleotide and Oligonucleoside Synthesis

[0109] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.

[0110] Oligonucleotides: Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0111] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w / v solution of 3,H-1,2-benzodith...

example 3

RNA Synthesis

[0113] In general, RNA synthesis chemistry is based on the selective incorporation of various protecting groups at strategic intermediary reactions. Methods of RNA synthesis are well known in the art (Scaringe, S. A. Ph.D. Thesis, University of Colorado, 1996; Scaringe, S. A., et al., J. Am. Chem. Soc., 1998, 120, 11820-11821; Matteucci, M. D. and Caruthers, M. H. J. Am. Chem. Soc., 1981, 103, 3185-3191; Beaucage, S. L. and Caruthers, M. H. Tetrahedron Lett., 1981, 22, 1859-1862; Dahl, B. J., et al., Acta Chem. Scand., 1990, 44, 639-641; Reddy, M. P., et al., Tetrahedron Lett., 1994, 25, 4311-4314; Wincott, F. et al., Nucleic Acids Res., 1995, 23, 2677-2684; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2301-2313; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2315-2331).

[0114] RNA antisense compounds (RNA oligonucleotides) of the present invention can be synthesized by the methods herein or purchased from Dharmacon Research, Inc (Lafayette, Colo.). Once synthesized,...

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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.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. provisional patent application Ser. No. 60 / 559,863, filed Apr. 5, 2004, which is incorporated herein by reference in its entirety.INCORPORATION OF SEQUENCE LISTING [0002] A computer-readable form of the sequence listing, on diskette, containing the file named RTS-0531US_Sequence_Listing.txt, which is 35,328 bytes (measured in MS-DOS) and was created on Mar. 31, 2005, is herein incorporated by reference. FIELD OF THE INVENTION [0003] The present invention provides compositions and methods for modulating the expression of transthyretin. In particular, this invention relates to antisense compounds, particularly oligonucleotide compounds, which, in preferred embodiments, hybridize with nucleic acid molecules encoding transthyretin. Such compounds are shown herein to modulate the expression of transthyretin. BACKGROUND OF THE INVENTION [0004] Steroid hormones, thyroid hormones, retinoids, and vitamin D ar...

Claims

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Application Information

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IPC IPC(8): A61K48/00C07H21/02C12N15/113C12Q1/68
CPCC12N15/113C12N2310/11C12N2310/315C12N2310/321Y10T436/143333C12N2310/341C12N2310/346C12N2310/3341C12N2310/3525C12N15/1136C12Q1/6883C12Q2600/136C12Q2600/158
Inventor BROWN-DRIVER, VICKIEJAIN, RAVI
Owner IONIS PHARMA INC
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