Treatment strategy with the SGLT2 inhibitor in a GSD1b mouse model to correct metabolite-repair deficiency affecting neutrophils and kidney function

Glycogen storage disease type 1b (GSD1b) is a rare disease for which there is no effective cure. The supportive therapies so far available increase the chronicity of the disease and have a high impact on daily patients’ lives.  In particular, neutropenia and neutrophil dysfunction lead to severe infections and IBD, with heavy consequences on patients’ quality of life. Treatment with Granulocyte Colony Stimulating Factor to correct neutropenia not only is inefficient for many patients but it may increase the risk of myeloid neoplasm. Moreover, the disease severely affects kidney function leading to renal failure, dialysis or transplantation. Thus, more efficient and less toxic therapies are deemed. In this respect, the use of gliflozins has been recently proposed as an alternative drug to treat neutropenia. However, the role on neutrophils function is still not completely elucidated together with the safety profile and the potential benefit on kidney and liver. Indeed, our preliminary data indicate that the kidney may be a central target of gliflozins and, as a consequence, it could potentially drive a systemic benefit. In this study, we aim to address these questions in a mouse model of GSD1b. To this end, a global analysis of system biology on the kidney and neutrophils’ function in response to treatment with gliflozins will be performed. This will allow deriving important information on the safety of gliflozins in GSD1b together with highlighting unknown mechanisms of the disease. This latter point is a fundamental step to increase the therapeutic options for GSD1b patients.