Inhibition of the Ire1alpha-XBP1 Pathway Using Toyocamycin as a Novel Way to Inhibit Progression of Autosomal Dominant Polycystic Kidney and Liver Disease
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is part of a family of genetic fibrocystic disorders that primarily affect the kidney and liver. The disease causes abnormal growth to fluid-filled sacs (cysts) in the kidney and liver that grow over decades. People affected with this disease develop a number of symptoms related to the growth of these cysts that include high blood pressure, abdominal pain, and chronic kidney disease that eventually leads many patients to require dialysis or kidney transplantation. Over 600,000 people are affected by this disease in the United States and currently only one medication has been approved for the treatment of ADPKD, i.e., tolvaptan; unfortunately the safety and efficacy profile of this therapy is modest and better, more innovative modalities for tackling the disease are desperately needed. The mutated genes associated with ADPKD have been identified and much basic science research has been done to improve our understanding of what causes this disease in people. Our proposal focuses on a pathway, i.e., Ire1alpha-XBP1 that we have found to play an important role in controlling the viability of Pkd1 null cells. Genetic inhibition of this pathway in relevant mouse models of ADPKD led to a slowing down of disease progression and significantly improved kidney function via selective apoptosis of cystic epithelia. Furthermore, toyocamycin, a natural compound previously tested in human patients with no significant adverse events and which has been convincingly shown to inhibit the Ire1a endoribonuclease function displays very compelling preclinical efficacy in adult gold-standard ADPKD models. Based on these observations, we will investigate the molecular mechanism of the Ire1alpha-XBP1-dependent pro-apoptotic phenotype seen in the absence of Pkd1 (Aim 1); refine the therapeutic profile of toyocamycin through dose-response and longitudinal efficacy studies (Aim 2); test the effect of genetic and chemical inhibition of Ire1alpha on the progression of polycystic liver disease due to PC1/PC2 deletion. Our proposal is very relevant to one of the FY20 PRMRP highlighted Topic Areas, i.e., ADPKD, and is bound to generate both molecular insights into a pathway that holds cystic disease modifying potential and also preclinical efficacy evidence for a previously human-tested compound in the context of ADPKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210005
Entities
People
- Sorin Fedeles
Organizations
- United States Army
- Yale University