Prof. Massimo Federici, University of Roma TorVergata; Dr Rossella Menghini, University of Roma TorVergata; Dr Viviana Casagrande, University of Roma TorVergata; Dr Stefano Menini, University of Roma La Sapienza
University of Roma TorVergata
Diabetic nephropathy is among the top three causes of terminal kidney disease in the Western world. Nephropathy occurs in 35% of patients with type 2 diabetes and as many as 44% of patients undergoing dialysis are diabetic. The clinical and pathological hallmarks of DN are progressive albuminuria, a gradual decline in glomerular filtration rate (GFR) and podocyte loss. Tissue inhibitor of Metalloproteinase 3 (TIMP3) is an Extracellular matrix (ECM)-bound protein that is involved in a wide range of physiological processes. We have already demonstrated that loss of TIMP3 contributes to the onset and progression of diabetic kidney disease (DKD) in human patients and in mouse models of diabetes. There is currently no specific therapy for diabetic nephropathy and the ability to restore high TIMP3 activity specifically in the kidney through a specific carrier peptide, may represent a potential therapeutic strategy for the amelioration of renal injury under conditions, such as diabetic nephropathy, in which its reduction is directly related to the disease.
The invention consists of a fusion between a peptide carrier highly selective and efficient for transport to the kidney and the N-terminal of a peptide derivative of the human protein TIMP3. This peptide allows to restore high TIMP3 activity in the kidney under conditions, such as diabetic nephropathy, in which its reduction is directly related to the disease. In in vivo mouse model of long-term diabetic renal pathology, drug treatment is associated to a significant and consistent decline in albuminuria along with improved glomerulosclerosis and tubulointerstitial fibrosis. Anti-inflammatory, anti-fibrotic and anti-oxidative effects of the drug are exerted through a mechanism independent from glycemic control. No toxic effects have been observed at behavioral level and through hematological and biochemical analysis.
This invention has a possible industrial application consisting in the development of a drug for the prevention and treatment of diabetic nephropathy. In Italy it is estimated that about 1,000,000 subjects present the clinical criteria (incipient nephropathy, stage II) to use this type of therapy. Preventing or otherwise delaying kidney injury and dialysis would have a significant economic impact in terms of savings for the National Health Service. There are no currently available drugs specifically designed for diabetic nephropathy.
The drug efficiency for diabetic nephropathy has been validated in preclinical phase on animal models. Current studies involve a 3 dimensional (3D) podocyte-endothelial cell co-culture model to understand whether animal data could be extrapolated to human system. Once these steps are defined phase I and phase II trials in human subjects will be considered.
An international application has been filed (PCT/IB2019/050482)
1. Geng Q et al. Peptide-drug conjugate linked via a disulfide bond for kidney targeted drug delivery. Bioconjug Chem. 2012;23:1200-10.
2. Janzer M et al. Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers. Bioconjug Chem. 2016;27:2441–9.
3. Fiorentino L et al Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med. 2013 Mar;5(3):441-55.