Development of a therapy based on mesenchymal stem cells transfected with plasmids containing the HGF and Klotho genes conjugated to nanoparticles aiming the treatment in an animal model of Diabetic Nephropathy

Abstract

Diabetes Mellitus (DM) is a chronic disease that affects people from all ages, gender and ethnicity. DM is predicted to be the 7th leading cause of death in 2030. DM is associated with micro- and macrovascular complications, such as diabetic nephropathy (DN). DN is a multifactorial disease, progressive and extremely complex, that induces morphological alterations and renal dysfunction. DN is the main cause of End Stage Renal Disease (ESRD). DN treatment is a scientific challenge, once there is no specific strategy available that can revert or interrupt the disease progression. Current available strategies may slow the progression of DN, although approximately 30 - 40% of diabetic patients develop ESRD. Cell therapy is a potential strategy to treat DN, once that therapy may modulate processes involved in complex diseases. The utilization of Bone Marrow-derived Mesenchymal Stem Cells (BM-MSC) has been largely documented in several animal models, including the models of DN. Thus, BM-MSC therapy may lead to improvement of functional and morphological aspects in DN setting. Therefore, cell therapy has the potential to provide another source of cells for tissue regeneration, since the number the patients with ESDR increases annually and there is a shortage of available kidney donors. To note, the administration of BM-MSCs combined to renal progenitor/stem cells has the potential to halt the progression of acute and chronic disease, including DN. Of importance, BM-MSCs can be genetically modified, which ultimately contribute to increase their paracrine effects on damaged kidneys. Thus, this project pursues novel hypotheses, which include (1) verify the therapeutic potential of genetically modified BM-MSC with the anti-aging protein Klotho and with the growth factor Hepatocyte Growth Factor (HGF) combined to nanoparticles in the animal model of DN of leptin knockout mice; (2) investigate if that treatment has the potential to enhance the therapeutic potential of kidney-derived c-Kit stem/progenitor cells. Our project is innovative because BM-MSC cell therapy combined to gene therapy and nanoparticles may be therapeutically utilized to treat DN. The results obtained from this research proposal will set the basis for establishing further investigation involving the therapeutic potential of BM-MSC and c-Kit+ progenitor/stem cells for treatment of DN in preclinical and clinical studies. (AU)