Molecular characterization of the long-term onset of nephropathy and new treatments in glycogen storage diseases type 1 – GSD1Nephro

Glycogen storage disease 1a (GSD1a) is a rare metabolic disease due to glucose-6 phosphatase (G6PC) deficiency and it is characterized by short fasting hypoglycemia. Since the 80’s, life expectancy of GSD1a patients has improved considerably thanks to frequent carbohydrate-rich meals and intense nutritional management. Nevertheless, these patients develop long-term chronic kidney disease, eventually leading to renal failure. Renal transplants or dialysis is the only treatment for these patients.
Living with an advanced renal disease has important negative impacts on the quality of life and it represents a frequent cause of morbidity. Until recently, the molecular mechanisms involved in GSD1a nephropathy remained unclear, since the GSD1a animal models were hardly viable after weaning. Because of this, we recently developed a mouse model with a G6pc deletion specifically in the kidneys (K.G6pc-/- mice). K.G6pc-/- mice are viable and develop the same renal complications as GSD1a patients. K.G6pc-/- mice exhibit a progressive deterioration in renal functions initiated by early tubular dysfunction, later on by a filtration barrier injury, and finally by glomerulosclerosis development. Then, K.G6pc-/- mice develop renal failure and polycystic kidneys with age.

The goal of this project is to improve the diagnosis and treatment of GSD1a patients, by a better understanding of the renal pathology. Using the K.G6pc-/- mice, we can: 1) decipher the molecular mechanisms responsible for the renal pathophysiology; 2) study the effect of diet on these molecular pathways, as well as the progression of the pathology; 3) identify therapeutic targets; 4) identify biomarkers specific for the early stages of the renal pathology, that will allow an early pharmacologic intervention when needed in patients; and 5) develop new gene therapy strategies, including CRISPR/cas9-based genome editing. We would also like to propose an elaboration of a register of GSD1 patients, and a creation of a bio-bank (blood and urine samples) with the agreement of the GSD1 patients registered in the “Centre de référence des maladies héréditaires du métabolisme hépatique (Paris)”, in order to follow the development of nephropathy in GSD1a patients.

There are many anabolic pathways that are hyper-activated in the renal tubules due to the excess in glucose-6 phosphate. We will focus on the role of lipid accumulation (lipidomics), and their effects and consequences on the cellular defenses in K.G6pc-/- kidneys. Recently, several new early biomarkers were established in other chronic kidney diseases. We intend to test these biomarkers in K.G6pc-/- mice and in GSD1 patient samples before the microalbuminuria stage, and evaluate if we can develop a more finely-tuned diagnosis method. In order to improve and unify the nutritional advice given to patients, we will study the effect of different diets on the progression of the nephropathy and the renal metabolism as a whole. We also propose to study the effects of several pharmacological agents, alone or combined, in order to target the specific mechanisms involved in GSD1 renal pathology. Finally, the K.G6pc-/- mice are an excellent in vivo tool for testing new viral vectors for targeted gene replacement.

The outcome of these studies will be translated into new therapeutic pharmacological and dietary interventions, allowing us to improve the long-term outcome and, thereby the quality of life of GSD1 patients. Identification of biomarkers that appear earlier and are more sensitive could permit a better prevention of the deterioration of renal functions in GSD1 patients.