Novel Aminoglycoside Therapy of Nonsense Mutations in Polycystic Kidney Disease
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) affects about 1:750 people and is inherited as a dominant trait associated with mutations of PKD1 or PKD2 genes. Microscopic renal tubular cysts emerge prior to birth, but progressive cyst enlargement and renal dysfunction during adult life, usually leads to kidney failure by age 40-60 years. ADPKD accounts for 8%-10% of end-stage renal disease in North America, with all the attendant human and monetary costs of chronic renal failure, dialysis and transplantation. Applicants to the US military who are known to have ADPKD are not usually accepted. However, most ADPKD patients aren’t diagnosed until they are 30-40 years of age. Thus, ADPKD often becomes evident only after military recruits are well into their service career. ADPKD is associated with risk of cerebral aneurysm rupture, hypertension, kidney stones, and renal bleeding when flying at high speed, making it difficult for active personnel to perform their duties. ADPKD leads to progressive renal failure, requiring costly dialysis and kidney transplant therapy after retirement. It may also appear among family members of military personnel. Between 25%-30% of ADPKD is caused by a particular type of gene mutation, called a “Nonsense Mutation” (NSM). Interestingly, it has been known for >10 years that this type of mutation can be overcome by compounds related to the aminoglycoside antibiotic family. However, these drugs are too toxic to the kidneys and middle ear to be considered for long-term use. Remarkably, Baasov et al. have recently developed a series of new, nontoxic aminoglycosides that retain the ability to overcome NSM. In preliminary studies, the lead compound, ELX-02, dramatically overcame NSMs in cells from two other genetic disease models. The experiments proposed here are intended to show that ELX-02 could be used to treat the subset of ADPKD patients who have inherited NSMs in PKD1 or PKD2 genes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010125
Entities
People
- Paul Goodyer
Organizations
- McGill University Health Centre
- United States Army