The Kidney Foundation of Canada

Dr. Constantions Deltas 

Dr. Constantions Deltas

University of Cyprus, Nicosia, Cyprus

Repurposing of FDA approved chemical chaperones to the rescue of a mouse model of Alport syndrome


2017-2019:  $100,000  |  Alport Syndrome Foundation Grant  |  Category: Alport Syndrome

Biography

Prof. Deltas graduated in 1982 from the National and Kapodistrian University of Athens with a degree in Pharmaceutics. He then earned a PhD degree in Biochemistry, from Rutgers University, The State University of New Jersey, USA in January 1988. His PhD Mentor was Prof. Darwin J. Prockop, a well renowned scientist in connective tissue research. After a few more years in the USA, having worked at the Jefferson Institute of Molecular Medicine and at Duke University Medical Center, in 1991 he was offered a job at the newly established Cyprus Institute of Neurology and Genetics, in his home country, Cyprus. He was always fascinated by the DNA world and he was one of very few who first developed molecular medical diagnostics and genetics research in the Greek world, with emphasis on inherited kidney disorders. His work was instrumental in several related fields. He was involved in the mapping and cloning of the PKD2 gene; his group mapped the first gene for medullar cystic kidney disease (MCKD1 or MUC1) and has had major contribution in promoting the concept that familial “benign” hematuria is not always benign, associating hereditary forms of focal and segmental glomerulosclerosis and hematurias, with collagen IV mutations. His group showed for the first time a putative role of the unfolded protein response signaling cascade in Alport Syndrome and developed the first knock-in mouse model for Alport Syndrome. They are going to use these mice for a pre-clinical study of FDA approved chaperones with funding by the Alport Syndrome Foundation (ASF, USA), The Kidney Foundation of Canada and the Pedersen family.

Lay Summary

Dr. Constantinos Deltas, Professor of Genetics and Director of the Molecular Medicine Research Center at the University of Cyprus, was awarded $100,000 for an 18-month pilot study on Repurposing of FDA approved chemical chaperones to the rescue of a mouse model of Alport syndrome.

The mutations inherited by about 40-50% of patients with Alport syndrome, lead to defective collagen IV genes and abnormal folding and breakdown of the protein, before it gets to the basement membrane. The basement membranes are important structures of the kidney that serve a key role in blood filtration. Additionally, the misfolded collagen molecules also elicit an abnormal intracellular phenotype, triggering the hyper-activation of a related signalling cascade.

This research project aims to use small synthetic molecules, called PBA and TUDCA, as medicines to help improve the three-dimensional folding of the mutated collagen molecules and to promote its effective trafficking to the basement membrane, outside the cells. These medicines will be used to treat a mouse model of Alport syndrome that the researchers prepared and are studying in Cyprus. The effective secretion of collagen IV molecules in the extracellular basement membrane, even if they have a missense mutation, is hypothesized to improve the three-dimensional network and the long-term outcome of the kidney disease. Importantly, the medicines to administer to the mice, have been approved by the FDA for use in other human conditions, thus repurposing them may save time in proving their safe and efficacious application.