for Physicians
for Patients

Research Project

Project Title:

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

Project Type:

 Translational research

Disease group(s):

 Metabolic & stone disorders

Project Summary:

 Glycogen storage disease type 1b (GSD1b) is a rare genetic disease for which there is no effective cure. GSD1b is caused by loss of function of the glucose-6-phospate transporter (G6PT) gene. The clinical signs of high impact affect liver, kidney and the immune systems leading to frequent hospitalization and a poor quality of life. Recent evidences indicate that gliflozins, a new class of glycosuric agents effective to treat diabetes mellitus could ameliorate neutropenia and neutrophil dysfunction in GSD1b patients. No data are currently available on liver and kidney function. Our preliminary data suggest that treatment with dapagliflozin, a highly selective SGLT2-inhibitor, prevents glycogen accumulation in renal proximal tubules and ameliorates renal symptoms in a mouse model of GSD1b. However, all these evidences are still preliminary and a large set of data are required
to validate the complex metabolic and potential toxic off-target effect standing behind the use of gliflozins in
GSD-1b patients. Thus, we propose to use a mouse model of GSD1b to evaluate the effects of dapagliflozin on neutrophils, kidney, and liver functions in terms of therapeutic effects and toxicity. In addition, by a system biology approach, we aim to derive the metabolomic, proteomic, and mitochondrial activity profiles of renal proximal tubules in order to highlight crucial metabolic pathways.The utilization of an animal model is the cornerstone for progressing in the quest for treatment. In this particular instance this mouse model will allow to evaluate the molecular basis and the effects of these drugs on the progression of the disease.

Lead principal investigator(s):

 Francesco Trepiccione, Naples

Co-investigator(s):

 Alessandra Eva, Genova

Project Period:

 09/2020   -   08/2021

Sponsors:

 Non-profit foundation

Project web page:

 https://www.telethon.it/cosa-facciamo/gestione-della-ricerca/bandi-di-ricerca/iniziativa-spring-seed-grant-con-le-associazioni-di-pazienti/
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