Development of new strategies for the treatment of Primary Hyperoxaluria Type I

Primary Hyperoxaluria Type I (PH1) is a life-threatening rare disease, whose principal hallmark is the formation of calcium oxalate crystals at first in the kidney and urinary tract and then in the whole body; it is caused by the deficiency of hepatic alanine:glyoxylate aminotransferase (AGT), which detoxifies glyoxylate to glycine. The only two curative treatments now available for PH1 are pyridoxine therapy, that is effective in only 10-30% of the patients, and liver transplantation, that is a very invasive and problematic procedure. Although these therapies have greatly advanced the clinical management of the patients, much remains to be learned on the disease mechanisms and response to treatment. The present grant application proposes a multi-disciplinary study to causally relate the effects of mutations in AGT not only with disease progression and severity, but also with the responsiveness to pyridoxine therapy. The achievement of this goal will greatly improve the clinical management of PH1 patients by facilitating the choice of the right treatment. In parallel, the present project proposes two novel therapeutic approaches as alternatives to liver transplantation for pyridoxine-unresponsive patients. The first approach is based on the use of compounds, named pharmacological chaperones, that help AGT to acquire its functional conformation and can be regarded as an “enhancement therapy”. It would be useful for pathogenic mutations that prevent a correct folding of the protein. The second approach is based on the engineering of AGT-bound nanoparticles that could be administered to PH1 patients and supply the liver with a functional enzyme. This "replacement therapy" would normalize the metabolism of glyoxylate and revert the progression of the disease. The participants to the research are experts in the field of PH1 pathogenesis and have a long-time experience in the different fields required for the development of the project.