Development of 2-Deoxy-D-Glucose for the Treatment of Polycystic Kidney Disease
Abstract
This proposal is focused on developing a new drug for the treatment of autosomal dominant polycystic kidney disease (PKD), which is a FY21 PRMRP Topic Area. PKD is an inherited disease characterized by the growth of fluid-filled sacs called cysts, within the kidney. This causes pain, bleeding, infections, and eventually leads to kidney failure. There is only one drug that has so far been approved for PKD, tolvaptan, but it has many side effects, it has limited efficacy and can significantly worsen the quality of life of those under this medication. So, there is a need for better drugs. We have discovered that one of the mechanisms driving expansion of cysts in this disorder is mediated by changes in the sources of energy for the cell. More specifically, we have found that cells of the cysts are addicted to a simple sugar (called glucose) and cannot generate energy through any other source (such as proteins or fat). Based on this, we have designed a new therapy using a compound that resembles glucose, called 2-deoxy-D-glucose (2-DG for short). Cystic cells exposed to this sugar-like molecule will be fooled by the similarity with glucose and pick it up from the environment in large amounts. Once inside the cell, however, this compound blocks entirely the capability of the cells to generate energy. We like to compare 2-DG to a small Trojan horse, able to break the security code of the cells and block their functionality. Over the years, we and others have demonstrated that 2-DG greatly retards disease progression in multiple different animal models of the disease. Here, we seek support to perform the last preclinical studies required by the Food and Drug Administration (FDA) to precisely define the appropriate therapeutic window of safety/efficacy that could be translated into humans. The ultimate goal is to obtain approval from the FDA to formally test whether 2-DG administered at safe doses, as defined through the current funding, in an autosomal dominant PKD (ADPKD) patient population achieves the very significant amelioration of disease progression that one would predict based on animal studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210389
Entities
People
- Alessandra Boletta
Organizations
- San Raffaele Hospital
- United States Army