An MMP-2 Inhibitory Biologic for Treatment of Renal Disease

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Abstract. Renal fibrosis is the final common pathway of all chronic and progressive kidney damage nephropathies and is marked as excessive buildup of scar formation, replacing the functional tissue. These conditions are induced and further exacerbated by cardiovascular diseases and hypertension. Renal scarring eventually leads to end state renal disease, for which there are very limited and expensive therapeutic options such as dialysis and kidney transplant. The high number of patients with kidney disease that progress to requiring dialysis or transplant highlights the great need for drug development in this area. Matrix metalloproteinases (MMP’s) are a class of enzymes that cleave the extracellular matrix components and other bioactive molecules and are found to be upregulated during the initial stages of renal diseases. Although upregulation of some MMPs can be anti- fibrotic, MMP-2 activation has been shown to be pro-fibrotic at early stages of renal injury. MMP-2 can process profibrotic cytokines such as transforming growth factor beta and tumor necrosis factor alpha and beta to enhance inflammation and fibrosis. A selective MMP-2 inhibitory peptide (APP-IP) was discovered that may have therapeutic effects against renal fibrosis. However, free peptides suffer from poor biodistribution and high clearance and degradation rates. To circumvent these issues, APP-IP will be fused with a biopolymer drug delivery system known as elastin like polypeptide (ELP), known to stabilize peptide therapeutics to improve their pharmacokinetics and to enhance renal targeting. Preliminary data show that the ELP-APP-IP fusion protein inhibits MMP-2 and accumulates in the cortical region of the kidney. Our lab has also demonstrated, using MMP- 2 knock out rats, that removal of MMP-2 activity prevents fibrosis formation in salt-sensitive hypertension. The goal of the proposed studies are 1) to develop three different sized ELP-APP-IP proteins with or without a kidney targeting peptide to identify the one with the greatest renal localization and MMP-2 inhibitory activity, and 2) to determine the efficacy of ELP-APP-IP by administering it to a established rat model of hypertension induced renal injury to determine if it prevents or reverses kidney fibrosis, ameliorates renal injury and improves kidney function.