(Press-News.org) Researchers have shown that dangerous cysts, which form over time in polycystic kidney disease (PKD), can be prevented by a single normal copy of a defective gene. This means the potential exists that scientists could one day tailor a gene therapy to treat the disease. They also discovered that a type of drug, known as a glycoside, can sidestep the effects of the defective gene in PKD. The discoveries could set the stage for new therapeutic approaches to treating PKD, which affects millions worldwide. The study, partially funded by the National Institutes of Health (NIH), is published in Cell Stem Cell.
Scientists used gene editing and 3-D human cell models known as organoids to study the genetics of PKD, which is a life-threatening, inherited kidney disorder in which a gene defect causes microscopic tubes in the kidneys to expand like water balloons, forming cysts over decades. The cysts can crowd out healthy tissue, leading to kidney function problems and kidney failure. Most people with PKD are born with one healthy gene copy and one defective gene copy in their cells.
“Human PKD has been so difficult to study because cysts take years and decades to form,” said senior study author Benjamin Freedman, Ph.D., at the University of Washington, Seattle. “This new platform finally gives us a model to study the genetics of the disease and hopefully start to provide answers to the millions affected by this disease.”
To better understand the genetic reasons cysts form in PKD, Freedman and his colleagues sought to determine if 3-D human mini-kidney organoids with one normal gene copy and one defective copy would form cysts. They grew organoids, which can mimic features of an organ’s structure and function, from induced pluripotent stem cells, which can become any kind of cell in the body.
To generate organoids containing clinically relevant mutations, the researchers used a gene editing technique called base editing to create mutations in certain locations on the PKD1 and PKD2 genes in human stem cells. They focused on four types of mutations in these genes that are known to cause PKD by disrupting the production of polycystin protein. Disruptions in two types of the protein – polycystin-1 and polycystin-2 – are associated with the most severe forms of PKD.
They then compared cells with two gene copy mutations in organoids to cells with only one gene copy mutation. In some cases, they also used gene editing to correct mutations in one of the two gene copies to see how this affected cyst formation. They found organoids with two defective gene copies always produced cysts and those that carried one good gene copy and one bad copy did not form cysts.
“We didn’t know if having a gene mutation in only one gene copy is enough to cause PKD, or if a second factor, such as another mutation or acute kidney injury was necessary,” Freedman said. “It’s unclear what such a trigger would look like, and until now, we haven’t had a good experimental model for human PKD.”
According to Freedman, the cells with one healthy gene copy make only half the normal amount of polycystin-1 or polycystin-2, but that was sufficient to prevent cysts from developing. He added that the results suggest the need for a second trigger and that preventing that second hit might be able to prevent the disease.
The organoid models also provided the first opportunity to study the effectiveness of a class of drugs known as eukaryotic ribosomal selective glycoside on PKD cyst formation.
“These compounds will only work on single base pair mutations, which are commonly seen in PKD patients,” explained Freedman. “They wouldn’t be expected to work on any mouse models and didn’t work in our previous organoid models of PKD. We needed to create that type of mutation in an experimental model to test the drugs.”
Freedman’s team found that the drugs could restore the ability of genes to make polycystin, increasing the levels of polycystin-1 to 50% and preventing cysts from forming. Even after cysts had formed, adding the drugs slowed their growth.
Freedman suggested that a next step would be to test existing glycoside drugs in patients. Researchers also could explore the use of gene therapy as a treatment for PKD.
The research was supported by NIH’s Nation Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of General Medical Sciences through awards R01DK117914, UH3TR002158, UH3TR003288, U01DK127553, U01AI176460, U2CTR004867, UC2DK126006, P30DK089507, R21DK128638, and R35GM142902; an Eloxx Pharmaceuticals Award; the Lara Nowak-Macklin Research Fund; and a Washington Research Foundation fellowship.
About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov .
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical and translational medical research, and is investigating the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.
NIH…Turning Discovery Into Health®
END
EL PASO, Texas (April 4, 2024) – Psychology researchers at The University of Texas at El Paso are making progress towards understanding the biological underpinnings of depression, a leading cause of disability that affects approximately 280 million people around the world.
In a study published this April in the Journal of Affective Disorders, UTEP psychologist Sergio Iñiguez, Ph.D., and his co-authors make the case that prairie voles, small rodents that are found throughout the central United States and Canada, can be effectively used as animal models to further the study of ...
Human activity is changing the way water flows between the Earth and atmosphere in complex ways and with likely long-lasting consequences that are hard to picture.
Land use change is altering where clouds form and how precipitation is distributed. Meanwhile, weather modification activities like cloud seeding are shifting how nations plan for water use in the face of climate change. These and other changes to the planet’s atmospheric water cycle were once hard to imagine but are increasingly part of modern water management on the planet.
Colorado State University Assistant Professor Patrick Keys is an expert ...
Reston, VA—A new radiotheranostic system has the ability to detect and treat ovarian cancer noninvasively, according to new research published in the April issue of The Journal of Nuclear Medicine. Combining the highly specific huAR9.6 antibody with PET and therapeutic radionuclides, this theranostic platform may provide more personalized treatment to improve health outcomes for ovarian cancer patients.
Ovarian cancer causes more deaths than any other gynecologic malignancy, with a five-year survival rate below 30 percent for patients diagnosed at advanced stages. The current standard of care for ovarian cancer consists of surgery followed by platinum-based chemotherapy; however, ...
Research today doesn't only occur in a lab; indeed, many university researchers extend their work into the community with the goal of inspiring the next generation of scientists and engineers. And some government agencies, like the National Science Foundation, provide the funding to do so. Most recently, Xiayun Zhao, assistant professor of mechanical engineering & materials science at the University of Pittsburgh, completed such outreach at the Carnegie Science Center (CSC).
Zhao ...
RIVERSIDE, Calif. -- NeuroHIV refers to the effects of HIV infection on the brain or central nervous system and, to some extent, the spinal cord and peripheral nervous system. A collection of diseases, including neuropathy and dementia, neuroHIV can cause problems with memory and thinking and compromise our ability to live a normal life.
Using a mouse model of neuroHIV, a research team led by biomedical scientists at the University of California, Riverside, studied the effects of interferon-β (IFNβ), a small protein involved in cell signaling and integral to the body’s natural defense mechanism against viral infections. The researchers found that higher or lower than ...
CHAMPAIGN, Ill. — Public policies blocked many families of Mexican descent living in the U.S. from accessing vital services such as food and mental health care during the COVID-19 pandemic, even though these communities experienced some of the highest infection and mortality rates.
Thirty-eight perinatal women and mothers of young children were interviewed about the challenges they faced during the pandemic and proposed solutions to better meet the needs of their communities during future large-scale crises in a study led by University of Illinois Urbana-Champaign kinesiology and community health ...
The lab of Yongchao C. Ma, PhD, at Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago discovered a fundamental biological mechanism that could lead to new treatments for neurological diseases, such as spinal muscular atrophy (SMA) and autism, as well as different cancers. The study was published in the journal Human Molecular Genetics.
Dr. Ma’s team found that chemical modification of RNA (called RNA methylation) regulates mitochondrial ...
Despite their ancient ages, some stars orbiting the Milky Way’s central supermassive black hole appear deceptively youthful. But unlike humans, who might appear rejuvenated from a fresh round of collagen injections, these stars look young for a much darker reason.
They ate their neighbors.
This is just one of the more peculiar findings from new Northwestern University research. Using a new model, astrophysicists traced the violent journeys of 1,000 simulated stars orbiting our galaxy’s central supermassive black hole, Sagittarius A* (Sgr A*).
So densely packed with stars, the region commonly experiences brutal stellar collisions. ...
A team of researchers has uncovered alarming trends in the first range-wide genetic study of an endangered bee species. The study, led by Colorado State University and published in the Journal of Insect Science, will inform conservation and recovery efforts for the rusty-patched bumblebee – a species that was once common in the United States but has declined from about 90% of its historic range.
The rusty-patched bumblebee was the first bee species to be federally listed as endangered in 2017 through the U.S. Endangered Species Act. Its numbers dropped rapidly starting in the late 1990s, likely due to a combination of pesticides, ...
ST. LOUIS, MO., April 4, 2024 — Acidic soil caused by changing climate patterns threatens agriculture sustainability across the globe. But the problem goes far beyond rising temperatures. One major cause for concern is more acidic soil, a product of increasing rainfall. Acidic soils with low pH are widespread globally and common in tropical and sub-tropical regions, where food security is a serious challenge. Climate change has exacerbated the problem. Acidic soil can result in aluminum toxicity, putting further stress on global agriculture. A new collaborative research team from the US and Brazil received a $2 ...
