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COMPOSITIONS AND METHODS FOR REGULATING RNA TRANSLATION VIA CD154 CA-DINUCLEOTIDE REPEAT

The expression of CD154 (CD40 ligand), a member of the Tumor Necrosis Factor gene family, by activated T lymphocytes is critical in the development of humoral and cell-mediated immunity. CD154 blockade retards the development and progression of immune responses in an array of transplantation and autoimmune disease models ranging from Systemic Lupus Erythematosus to Rheumatoid Arthritis to Multiple Sclerosis. Overexpression of splice isoforms of polypyrimidine tract binding protein differentially regulate CD154 expression and mRNA accumulation in a 3'-UTR-dependent manner in cell lines and normal human T cells.

Dartmouth researchers have now found a novel pathway which regulates translation and nuclear export of CD154 mRNA. The mouse CD154 3’-UTR was found to contain two distinct cis-acting elements that reduce cytoplasmic mRNA accumulation, a CU-rich region which increases mRNA turnover and a CA-rich region which modulates mRNA translation. The protein binding to and regulating expression of CD154 via the CA-rich sequence was identified as the RNA binding protein hnRNP L. Thus, inhibiting CD154 expression at the level of hnRNP L or the CA-dinucleotide repeat can be used in the treatment of autoimmune and inflammatory diseases, whereas enhancing expression of CD154 by targeting this pathway can be used in immunotherapy of cancer or for augmenting immune responses in immunodeficient individuals. Moreover, targeting hnRNP L or the CA-dinucleotide repeat can be used in treatment of acute and chronic atherosclerotic disease including angina, myocardial infarction, stroke and other conditions of acute or chronic vascular insufficiency.

This technology is claimed in the published United States Patent Application Nos. 11/854,148 and 12/064,471. We are seeking an industrial partner interested in its commercialization. (Ref.: J323)


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