Defining glomerulus-homing peptides for targeted drug delivery in lupus nephritis

University Of Maryland Baltimore, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, or lupus) is a chronic debilitating systemic autoimmune disease involving inflammation and damage to the renal glomeruli and other tissues. Both autoreactive T cells and antibodies are involved in mediating the pathogenic effector responses in lupus. Two of the main challenges for researchers working in the field of SLE are - 1) to define the underlying mechanisms that render the renal glomeruli highly prone to an autoimmune attack, and 2) to devise novel ways to direct the orally-administered or injected drugs primarily to inflamed glomeruli to enhance their efficacy while minimizing adverse effects. We hypothesize that the vascular endothelium of the renal glomeruli is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ (the kidney) as well as enhanced interaction with the inducers/mediators of inflammation and tissue damage. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham, La Jolla & UCSB, CA; member, National Academy of Sciences), we recently completed and published (PNAS 2011, 108: 12857) a study of the synovial vasculature in the rat adjuvant arthritis model. The objective of that study was to identify unique joint-specific vascular endothelial markers using an innovative approach of in vivo enrichment of clones from a phage peptide-display library. This approach was pioneered by Dr. Ruoslahti, who has developed the concept of vascular 'address molecules' or 'zip codes' and has extensively applied it to the areas of tumor biology and tumor immunotherapy. The advantage of the phage system for detection of tissue-specific markers is that there is no a priori bias in predicting the ligand in the vascular endothelial or other cells. In addition, unlike antibodies, the phage- displayed peptides interact with the functional domain of the target molecule. We propose that the vascular endothelial cells of the inflamed renal glomeruli are characterized by unique molecular markers, and that the targeting of drugs via one or more of these markers would downregulate inflammation and tissue damage in the kidney without undue adverse reactions or systemic toxicity. The aims of our study based on two animal models of lupus, one induced and other spontaneous, are as follows: Aim 1. To identify unique 'address molecules' for the vascular endothelium of the target organ (the inflamed renal glomeruli) in mice with lupus using the in vivo screening of a phage peptide-display library. Aim 2. To use the phage-encoded peptides for targeted drug delivery into the inflamed renal glomeruli to control inflammation and tissue damage in the kidney. We believe that the results of this study would advance our understanding of the pathogenesis of lupus, and help designing novel therapeutic approaches for human lupus via translational research.