Genome-Wide CRISPR/Cas9 Viability Screen to Uncover Molecular Targets That Modulate the Survival of Polycystic Kidney Disease Mutant Cells
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. In our proposal, we will use an unbiased genetic screen via CRISPR/Cas9 to identify genes that help cystic cells survive and thus when inactivated lead to a decrease in their viability. This type of approach, i.e., specifically killing mutant cells while leaving wild-type counterparts intact, is very novel and in the future it may become either a stand-alone “pulse” treatment that would circumvent the need for continuous anti-proliferative therapies or it may also lead to “multi-drug” strategies that can be used to limit dosing requirements for any single drug and thereby keep the drugs well within their therapeutic indices. Our proposal is very relevant to one of the FY20 PRMRP highlighted Topic areas, i.e., ADPKD, and is bound to uncover pathways that regulate survival of cystic cells and that may hold disease-modifying potential.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2110088
Entities
People
- Sorin Fedeles
Organizations
- United States Army
- Yale University