Methods and sequences to suppress primate huntington gene expression

Abstract

Disclosed herein are sequences, molecules and methods used to suppress the expression of HD genes encoding for huntingtin protein in primates including Macaca mulatta and Homo sapiens. These sequences, molecules and methods aid in the study of the pathogenesis of HD and can also provide a treatment for this disease.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60 / 678,729 filed May 6, 2005.FIELD OF THE INVENTION [0002] The present invention relates to inhibitory nucleic acid molecules that suppress the expression of the Huntington's disease gene in primates, including rhesus monkeys (Macaca mulatta) and humans (Homo sapiens). BACKGROUND OF THE INVENTION [0003] Huntington's disease (“HD”) is a neurodegenerative brain disorder with a juvenile or adult onset. It slowly destroys an affected individual's ability to walk, think, talk and reason. Symptoms include changes in cognitive ability, such as impaired short-term memory and a decreased ability to concentrate; changes in mood, such as the development of mood swings, depression and irritability; and changes in coordination and physical movement such as clumsiness, involuntary movements and twitching. These symptoms gradually worsen until HD patien...

AI Technical Summary

Benefits of technology

[0009] The present invention describes methods, nucleic acid sequences and molecules, expression cassettes, and vectors for using RNA interference (“RNAi”) to suppress expression of the HD gene. Suppressing expression of the HD gene can reduce levels of huntingtin within cells. This suppression and reduction can be useful in the study of HD pathogenesis. This suppression and reduction also can be useful in the prevention and treatment of the symptoms of HD. Specifically, RNAi is mediated by double stranded RNA (“dsRNA”), short hairpin RNA (“shRNA”) or other nucleic acid molecules with similar characteristics. These nucleic acid molecules are processed or cut into smaller pieces by cellular enzymes including Dicer and Drosha. The smaller fragments of the nucleic acid molecules can then be taken up by a protein complex called the RNA-induced silencing complex (“RISC complex”) that mediates degradation of mRNAs. The RISC complex will degrade mRNA that complementarily base pairs with the nucleic acid molecules it has taken up. In this manner, the mRNA is specifically destroyed, thus preventing the protein for which the mRNA encoded from being made.

[0027] Another method of the present invention includes a method of preventing cytotoxic effects of mutant huntingtin in a cell comprising introducing a previously-described nucleic acid duplex into the cell in an amount sufficient to suppress accumulation of the mutant huntingtin so that the nucleic acid duplex prevents cytotoxic effects of mutant huntingtin in the cell.

[0030] Another method of the present invention includes a method of preventing cytotoxic effects of Huntington's disease (“HD”) in a Macaca mulatta or Homo sapiens comprising introducing a previously-described vector into a cell in an amount sufficient to suppress accumulation of a protein associated with HD, so that the resulting nucleic acid duplex prevents the cytotoxic effects of HD.

Problems solved by technology

It slowly destroys an affected individual's ability to walk, think, talk and reason.

If the mRNA is degraded quickly within the cell (such as before it reaches a ribosome), it is unable to serve as a template for new protein translation, thus reducing the cell's ability to create the protein for which it encoded.

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