24 Oct Gene-edited Kidney Organoids Re-Create Human Disease
MedicalResearch.com Interview with:
Benjamin Freedman, Ph.D.
Assistant Professor | University of Washington
Department of Medicine | Division of Nephrology
Member, Kidney Research Institute
Member, Institute for Stem Cell and Regenerative Medicine
Seattle WA 98109
Medical Research: What is the background for this study? What are the main findings?
Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy.
Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney ‘organoids’ that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific ‘symptoms’ of these two different diseases in the petri dish.
Medical Research: What should clinicians and patients take away from your report?
Dr. Freedman: Pluripotent stem cells are a new area for kidney study and care. We have shown that the cells can turn into primitive mini-kidneys that can perform certain basic functions of the kidney in a petri dish. What is perhaps more impressive is that these very simple tissues can actually re-create ‘symptoms’ of kidney disease, such as PKD cysts from tubules and junctional defects in glomerulonephritis. This is especially important because these types of cells are typically hard to grow and study in the lab.
Gene editing techniques like CRISPR allow us to modify the human genome, which is breathing new life into the field of gene therapy. In our study, the only difference between mini-kidneys that showed disease symptoms and those that did not was a small mutation in a single stretch of DNA. By inference, correcting disease in patients may be as simple as correcting a single gene. Technologies like CRISPR and pluripotent cells are in their infancy, and are not yet ready for the clinic, but might someday revolutionize the way we practice medicine.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Freedman: In the short term, our lab and others like it will use these genetically engineered mini-kidneys to investigate how diseases like PKD, glomerulonephritis, and nephrotoxicity actually work. The organoids can be produced in multi-well format, which raises the possibility of performing ‘clinical trials in a dish’ for thousands of candidate drugs to rescue disease symptoms. This high-throughput discovery approach will lead to better-informed and more successful clinical trials. The approach can be extended to many different types of kidney disease.
In the long term, pluripotent cells are a way to produce tissue on-demand that would be 100 % immunocompatible with the original patient. There is still a long way to go. The mini-kidney cells are trying to form a kidney nephron, but key structural components are missing or need to be integrated. We show in this study that mini-kidney tubules can survive after transplantation into mice. The holy grail is to further develop these grafts to be safe, efficacious, and disease-free for clinical use in human patients.
Benjamin S. Freedman, Craig R. Brooks, Albert Q. Lam, Hongxia Fu, Ryuji Morizane,Vishesh Agrawal, Abdelaziz F. Saad, Michelle K. Li, Michael R. Hughes, Ryan Vander Werff,Derek T. Peters, Junjie Lu, Anna Baccei, Andrew M. Siedlecki,Todd Valerius, Kiran Musunuru, Kelly M. McNagny, Theodore I. Steinman, Jing Zhou, Paul H. Lerou et al.
Benjamin Freedman, Ph.D. (2015). Gene-edited Kidney Organoids Re-Create Human Disease