Development of an inhibitory oligonucleotide for the treatment of lupus

DESCRIPTION (provided by applicant): Project summary/Abstract Systemic lupus erythematosus (lupus) is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age It is difficult to t reat and the few effective therapies have significant toxicities and side effects. The abnormal activation of two types of immune system cells, B lymphocytes and plasmacytoid dendritic cells (PDC) are important in the pathogenesis of the disease. The chron ic activation of both cell types appears due to stimulation by DNA and RNA acting through the innate immune receptors, TLR7 and TLR9. We have developed a series of synthetic oligonucleotides (termed IRS) with sequence motifs strongly inhibitory for both TL R7 and TLR9 signaling. In earlier work we characterized the specificity of IRS and provided rationale for the treatment of lupus based on animal model and human in vitro experiments. In the phase I SBIR grant, we developed an optimized and stabilized IRS m olecule, DV056, which we consider to be appropriate for clinical development. This proposal comprises several related activities to advance DV056 toward filing of an IND application for clinical trials, including: Assessing tissue distribution and pharma cokinetics with both acute and chronic dosing in a mouse model Measurement of pharmacodynamics of DV056 in mice Development of techniques for measuring bioactivity in both non-human primates and ultimately in man and assessment of pharmacodynamics in m onkeys Resolution of key outstanding questions about the mechanism of action of IRS. The ultimate goal is to use the results of this work, along with concurrent work at Dynavax on manufacturing and toxicology aspects, as the basis for initiating clinical trials in approximately 2 to 2,5 years. PUBLIC HEALTH RELEVANCE Systemic lupus erythematosis is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects, howev er recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that inhibits Interferon- alpha, a key factor in the disease.