UNEARTH PROJECT

FRRB Project 1745126 - A thorough understanding of the molecular players causing rare complement-mediated glomerular diseases toward a personalized therapy

PROJECT SUMMARY

Immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) are chronic kidney diseases for which there is no specific therapy. About 40% of patients needs dialysis within 10 years from diagnosis. The average annual cost per patient on dialysis is approximately €34,000. This value, significant both in terms of quality of life and impact on healthcare system, suggests the need to develop alternative treatments able to significantly delay the use of dialysis. Genetic alterations leading to an abnormal activation of the complement system, a component of the immune system, have been identified in approximately 20% of IC-MPGN/C3G patients. However, the molecular mechanisms through which these alterations cause the disease are yet unknown in most cases.

The aim of the UNEARTH project is to characterise the consequences on complement activation of the abnormalities identified in C3 and CFH-CFHR, the most frequently altered genes in IC-MPGN/C3G, and in IQGAP1, a new candidate gene we found altered in 6 patients. During the first 2 years, we obtained the recombinant C3 proteins and, as for CFH-CFHR hybrid proteins, evaluated their ability to modify the complement activation. We also evaluated the effects of the altered IQGAP1 protein in podocytes, the renal cells specialized in the blood filtration. We observed that abnormal IQGAP1 impacts on the podocyte cytoskeleton, a protein network that forms the cell scaffolding, and induces a deposition of complement on the surface of these cells when incubated with a serum sample. These results will characterise the pathogenetic mechanism underlying the disease in each patient, identifying the target molecule within the complement cascade and the suitable inhibitor among those in the clinical pipeline, in order to work towards developing personalised therapy and reducing the healthcare system costs.