Dallas: Researchers at UT Southwestern Medical Center, working with a California biotech firm, have developed a potential drug to treat polycystic kidney disease – an incurable genetic disease that often leads to end-stage kidney failure. The drug, now called RGLS4326, is in preclinical animal testing at San Diego-based Regulus Therapeutics Inc. An investigational new drug filing to pave the way for human clinical trials is expected later this year, said Dr. Vishal Patel, Assistant Professor of Internal Medicine at UT Southwestern.
Dr. Patel is senior author of a study describing research that led to the drug’s development, published online today in Nature Communications.
Affecting about 600,000 people in the U.S., autosomal dominant
polycystic kidney disease (ADPKD) causes numerous fluid-filled cysts to
form in the kidney. An affected kidney, normally the size of a human
fist, sometimes grows as large as a football. As their numbers and sizes
increase, these cysts eventually interfere with the kidney’s ability to
filter blood and remove bodily waste. The cysts can quietly grow for
decades until symptoms appear such as blood in the urine, Dr. Patel
said. About half of those affected with ADPKD suffer kidney failure by
age 60, according to the National Kidney Foundation.
“There isn’t a single drug on the U.S. market right now to treat the
disease,” Dr. Patel said. “Once your kidneys fail, your only option for
survival is to get a transplant or start dialysis.”
In 2009, Dr. Patel began searching for microRNAs that might underlie
progression of ADPKD. MicroRNAs – or MiRs for short – are tiny RNA
fragments that interfere with normal gene expression.
Proof that such RNA fragments even existed came in the early 1990s;
their presence in humans was first reported in 2000. Those discoveries
led to a groundswell of interest in developing drugs to treat diseases
caused by microRNAs, Dr. Patel said – in part because the process can be
straightforward once the problem-causing fragment is identified.
“Because miRs are so small, drugs can easily be designed against
them. And since we know the nucleotide sequence of every known microRNA,
all that is required is to prepare an anti-miR with a sequence that is
exactly the opposite of the miR’s,” he said.
In this study, researchers in Dr. Patel’s lab focused on microRNA
cluster 17~92 following identification of potential miR targets. A
National Institutes of Health grant funded the UTSW research. In 2013,
Dr. Patel and fellow researchers reported in Proceedings of the National Academy of Sciences that this microRNA cluster indeed appeared to promote kidney cyst growth.
Using four mouse models, the researchers next studied whether
inhibiting this microRNA could slow cyst growth and thus delay ADPKD
progression. They found that genetically deleting microRNA-17~92 slowed
cyst growth and more than doubled the life spans of some mice tested.
Based on that finding, Dr. Patel’s lab collaborated with Regulus
Therapeutics to test an anti-microRNA-17 drug. The test drug slowed the
growth of kidney cysts in two mouse models and in cell cultures of human
kidney cysts, the study showed.
In the Nature Communications study, UTSW researchers also
reported how miR-17 causes cyst proliferation: the molecule essentially
reprograms the metabolism of kidney cells so that cellular structures
called mitochondria use less nutrients, freeing up resources to instead
make cell parts that become cysts. MiR-17 accomplishes this by
repressing a protein involved in making RNA called peroxisome
proliferator-activated receptor alpha (PPARα), the researchers found.
Other UT Southwestern researchers included lead author Dr. Sachin Hajarnis, a research scientist; Dr. Ronak Lakhia,
Instructor in Internal Medicine; Matanel Yheskel and Andrea Flaten,
research technicians; Darren Williams, former research associate; Dr.
Shanrong Zhang, research engineer; Joshua Johnson, an M.D./Ph.D.
student; Dr. William Holland and Dr. Christine Kusminski, Assistant Professors of Internal Medicine; and Dr. Philipp Scherer,
Professor of Internal Medicine and Cell Biology, who holds the Gifford
O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in
Also contributing to the study were researchers from the University
of Minnesota Medical School, the Mayo Clinic School of Medicine, the
University of Montreal, the University of Kansas, and Regulus
Funding was provided by the National Institutes of Health (NIH) and
the PKD Foundation. Research reported in this publication was supported
by the National Institute of Diabetes and Digestive and Kidney Diseases
of the NIH under Award Number R01DK102572. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the NIH.
UT Southwestern and Regulus Therapeutics have applied for a patent
for treatment of polycystic kidney disease with miR-17 inhibitors. In
addition, Dr. Patel’s laboratory has a sponsored research agreement with
Regulus, and Dr. Patel serves as a consultant for Regulus.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the
nation, integrates pioneering biomedical research with exceptional
clinical care and education. The institution’s faculty includes many
distinguished members, including six who have been awarded Nobel Prizes
since 1985. The faculty of almost 2,800 is responsible for
groundbreaking medical advances and is committed to translating
science-driven research quickly to new clinical treatments.
UT Southwestern physicians provide medical care in about 80 specialties
to more than 100,000 hospitalized patients and oversee approximately 2.2
million outpatient visits a year.