National Yang Ming Chiao Tung University

Leland Stanford Junior University

Chia-Rung Liu

Tzu-Hao Cheng

Stanley N Cohen

Tzu-Han Wang

Yun-Yun Wu

Tse-I Lin

The present invention provides a method of modulating the expression of a gene containing expanded nucleotide repeats in a cell, comprising: inhibiting the biological activity of SPT4 or SUPT4H; and regulating the formation of R-loops. The inhibition step can effectively reduce the expression of the gene containing the expanded nucleotide repeats and the regulatory step can further enhance the inhibition step. The inhibition step and the regulation step are for the purpose of regulating gene expression by interfering the capacity of RNA polymerase II transcribing over a DNA template with lengthy nucleotide repeats.

Method to enhance the transcription regulation of SUPT4H on genes containing repetitive nucleotide sequences

Aspects of the invention include methods of selectively reducing the deleterious activity of mutant extended trinucleotide repeat containing genes in a cell, as well as compositions used in such methods. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended trinucleotide repeat containing gene may be selectively reduced in a variety of different ways, e.g., by selectively decreasing SPT4 mediated transcriptional activity, by enhancing functionality of proteins encoded thereby, etc. Aspects of the invention further include assays for identifying agents that find use in methods of the invention, e.g. as summarized above. Methods and compositions of the invention find use in a variety of different applications, including the prevention or treatment of disease conditions associated with the presence of genes containing mutant extended trinucleotide repeats, such as Huntington's Disease (HD).

Selective reduction of the deleterious activity of extended tri-nucleotide repeat containing genes

This invention provides a method for modulating the expression of a first gene in a cell wherein the first gene is one containing more than 36 CAG trinucleotide repeats and encoding a protein that form polyglutamine-mediated protein aggregation. Suppression of the first gene is achieved by reducing the expression of SPT4 gene or SUPT4H gene. It can also be achieved by inhibiting the formation of a Spt4/Spt5 complex or a Supt4h/Supt5h complex. Also provided is a method for identifying an agent useful for modulating the expression and aggregation of CAG-expanded gene product, or treating a polyglutamine disease such as Huntington's disease.

Methods for identifying agents useful for modulating the expression and aggregation of CAG-expanded gene product in cells

This invention provides recombinant protein comprising formula as follows:A-Bwherein A is polypeptide containing glutamine-rich domain comprising 8-200 glutamine residues and B is color-alteration enzyme modulated by the domain. This invention also provides an expressing vector and a cell produced therefrom. This invention further provides a method and a kit for screening a therapeutic agent for a neurodegenerative disease.

Growing community of inventors

Tainan, Taiwan

Chia-Rung Liu