Miniature lab-created kidneys offer researchers multiple new ways to advance precision medicine research
Two important studies, published just two days apart, illustrate the importance of organoids in advancing precision medicine-related kidney research. One study used kidney organoids to identify new medicines that could be used to treat polycystic kidney disease, clusters of cysts on the kidneys; the other used kidney organoids to identify what causes the development of tuberous sclerosis complex, a disease causing tumors that affect the kidneys.
The more recent of the two studies was conducted by researchers from the Keck School of Medicine at the University of Southern California (USC). Led by stem cell biology and regenerative medicine specialist Andrew P. McMahon, PhD, the researchers explored potential new treatments for polycystic kidney disease.
Polycystic kidney disease (PKD) is a progressive genetic disease that causes large cysts to develop on the kidneys, affecting their function and eventually causing kidney failure. While there is one medication that slows the progression of this disease in a genetic subset of the condition, there are not many good treatment options. Autosomal dominant PKD (ADPKD) is the most common genetic form of this condition and was the focus of the USC team’s research.
Using Engineered Organs to Discover New Medications
To try to find new medications that could treat ADPKD, researchers at the Keck School of Medicine developed kidney organoids that could be used to trial many new medicines. Organoids are small organs grown from stem cells. The kidney organoids developed by these researchers contained one or two nephrons, the filtering unit of the kidney, that actually functioned similarly to nephrons in the kidneys.
“These organoids are simple, reproducible, scalable, and cost-effective,” said McMahon, in a USC statement. “Most importantly, the organoids can consistently recapitulate key aspects of normal human kidney development, as well as cyst formation in ADPKD.”
Kidney organoids allow testing to be performed in a situation that mimics the real-life environment of the kidneys but does not require testing in humans. The organoids consist of human cells, allowing more realistic testing than testing using animals.
USC Researches Potential Treatments for Polycystic Kidney Disease
The USC research team tested over 240 different compounds on the organoids that they developed, attempting to inhibit the growth of cysts in the organoids without actually affecting the organoids themselves. According to the study, recently published in Cell Stem Cell, titled, “A Scalable Organoid Model of Human Autosomal Dominant Polycystic Kidney Disease for Disease Mechanism and Drug Discovery,” there were nine different compounds that showed promise, with one in particular, quinazoline, indicating a high level of effectiveness.
To make the organoids useful for studying ADPKD, the scientists used CRISPR/Cas9 gene editing. As anticipated, the gene-edited organoids began to form cysts, which eventually detached and grew to centimeters in diameter, according to the USC statement.
Researchers say the use of organoids enabled them to quickly and effectively identify potential compounds that could be used to treat ADPKD. “In the future, organoids will become an increasingly powerful tool for modeling and understanding human disease, identifying potential treatments, and eventually, providing transplants to replace organ function for patients,” said Tracy Tran, PhD, who participated in the study as a PhD student in the McMahon Lab, prior to successfully completing her PhD defense.
Researching Origins of Tuberous Sclerosis Complex
Like the USC research, the second recent study also used kidney organoids, but in a different way. Researchers from The Ottawa Hospital and the University of Ottawa used the organoids they created to gain insight into the development of tuberous sclerosis complex (TSC), a rare type of disease that primarily affects the kidneys.
TSC is a rare genetic disorder that causes benign and very unusual and diverse tumors to develop in many areas of the body. The effect of these tumors ranges from mild to severe. According to the National Institute of Neurological Disorders and Stroke, many people with TSC show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.
“The cells at the origin of tuberous sclerosis tumors have been a mystery for decades,” said senior author William Stanford, PhD, lead researcher of the study, in a News Medical article. “Our results can help find possible treatment targets for this challenging disease.” Stanford is senior scientist and professor at The Ottawa Hospital Research Institute, and founding and current director of the Ottawa Human Pluripotent Stem Cell Facility, according to his bio.
Renal Organoid Modeling at Ottawa
The use of kidney organoids enabled researchers to study TSC where it has the most impact in the body. “Kidney disease is the leading cause of death in patients with TSC,” explained Adam Pietrobon, first author of the study and an MD-PhD student at The Ottawa Hospital and the University of Ottawa.
“Around 60 to 80 percent of patients develop tumors in their kidneys, often reducing kidney function and sometimes leading to catastrophic bleeding,” Pietrobon said. “There were no adequate lab models to study how TSC affects the kidney, so we made one ourselves.”
Using kidney organoids, the researchers found a link between Schwann cell precursors in the kidneys and TSC tumors that begin in the kidneys. The single mutation affecting these cells impacts the development of many kinds of cells, explaining how the mutation causes the diversity seen in TSC tumors. See more, including this study’s limitations, in “Renal Organoid Modeling of Tuberous Sclerosis Complex Reveals Lesion Features Arise from Diverse Developmental Processes,” published in Cell Reports.
Pietrobon explained that kidney organoids offer the ability to test new treatments in the future. “Not only can these ‘mini-kidneys’ help us to better understand this disease, they can also be used to test new therapies,” he said.
Healthcare and nephrology leaders should be aware of how organoid technology is continuing to develop and how it is being applied to new research. Organoid technology will play a growing role in new precision medicine advances and in how patient-specific treatments are tested.