Mechanism of Action of Anti-miR-17 Human Drug Candidate
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is among the most common monogenetic human disorders. Nearly 600,000 Americans and ~2000-4000 military personnel are affected by ADPKD. ADPKD is characterized by massive bilateral kidney enlargement due to the presence of innumerable fluid-filled cysts in the renal parenchyma. Unfortunately, treatment options are limited, and the relentless cyst growth leads to end-stage renal failure (ESRD) in ~50% of patients. We have recently identified miR-17, a microRNA (miRNA) with oncogenic properties, as a novel drug target for ADPKD. This work has led to the development of an anti-miR-17 drug candidate. The goal of this proposal is to define the mechanism of action of this compound. MicroRNAs (miRNAs) are short non-coding RNAs that bind to target mRNAs and inhibit their function. We have recently shown that miR-17 is upregulated in mouse and human ADPKD. miR-17 genetic deletion inhibits cyst proliferation, improves renal function, and prolongs survival of four mouse models of ADPKD. Based on these studies, we have collaborated with a biotech company to develop and test an anti-miR-17 compound, which directly inhibits miR-17. Systemic injection readily delivers the compound to kidney cysts. We found that anti-miR-17 treatment slows cyst growth in three mouse models of PKD, including in a long-term model that was treated for ~6 months. Long-term treatment did not produce liver or kidney toxicity. Anti-miR-17 treatment also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. These promising results have led to the development of an anti-miR-17 human drug candidate, RGLS4326. Investigational New Drug (IND)-enabling toxicology studies are completed, and a Food and Drug Administration application, paving the way for human testing, is expected to be filed in late 2017. This application will address two questions of major scientific significance that must be answered as we advance the anti-miR-17 drug to human trials: (1) How does anti-miR-17 mediate its cyst-reducing effects? We need more mechanistic understanding of this compound. (2) Are there intermediate biomarkers to predict its therapeutic efficacy? Cyst growth is too distal a read-out. Based on our published work, we hypothesize that the key mode of action of anti-miR-17 is to normalize cyst metabolism, at least in part, by restoring PPARa expression. Moreover, improvement in parameters of metabolism may be harnessed as early biomarkers of anti-miR-17 efficacy. If successful, our work will have substantial short-term and long-term impacts. Our work will lead the development of an entirely new drug class for cystic kidney diseases, and thus has the potential of having a tremendous impact on the lives of patients with ADPKD. We will also uncover miRNA-mediated regulation of cyst metabolism as a novel a mechanism for cyst growth and generate innovative reagents/resources for the research community.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810673
Entities
People
- Vishal Patel
Organizations
- United States Army
- University of Texas Southwestern Medical Center