October 1, 2019
Nearly 40 million Americans are impacted by chronic kidney disease, a family of progressive conditions associated with widespread health complications, including higher risk for heart disease. When kidneys fail, the primary interventions, dialysis and kidney transplants, are not cures and come with significant side effects and a heavy economic burden ($114 billion a year in Medicare costs). Altogether, kidney disease is the ninth leading cause of death nationwide.
Now, major funding from the NIH will fuel an exciting new project that will allow scientists at UW Medicine to help pave the way for a game-changing approach to treating inherited kidney diseases – a significant and growing health crisis: 15% of kidney disorders are caused by a single-gene mutation, and other mutations contribute to the risk of chronic kidney disease.
Specifically, the four-year grant will support a collaborative effort between the University of Washington and the University of California, Berkeley to use kidney organoids to predict the adverse effects of genome editing, enhancing the safety of a future approach to treating inherited kidney diseases. The project is part of a new NIH consortium known as SCGE (Somatic Cell Genome Editing) that will focus on developing safe, effective genome editing technology and moving therapies to the clinic.
The UW research team will be led by Benjamin Freedman PhD, an Assistant Professor in Medicine/Nephrology, the Kidney Research Institute, and the Institute for Stem Cell and Regenerative Medicine (ISCRM). Freedman and his lab have invented stem cell-derived organoids to study how kidney diseases begin and how they can be treated. Human kidney organoids and kidney-on-a-chip technology have already yielded encouraging results, including the identification of new molecules that reduce symptoms of genetic disease in these systems.
Exploring Responsible Gene-editing Therapies for Inherited Kidney Diseases
Collectively, Freedman and the other UW researchers bring an expertise in kidney organoids, the cell biology of the kidney, and the nature of kidney disease. Their counterparts at UC Berkeley are leaders in the field of genome editing, including Jennifer Doudna, PhD, a Professor in the Departments of Chemistry and of Molecular and Cell Biology, who invented CRISPR-Cas9 gene editing technology to readily ‘cut and paste’ DNA in living cells.
Freedman explains the importance of exploring responsible gene-editing therapies for inherited kidney diseases. “Genetic kidney diseases impact more than half a million people in the United States alone. If we can learn to safely repair the mutation that causes the disease, we can offer a way to treat patients that is much more effective than any current intervention.” Freedman emphasizes that dialysis and transplants – two of the most common treatments for kidney diseases – are expensive, hard on patients, and in short supply (kidney transplants are available to less than 20% of patients each year).
The shortcomings of dialysis and transplants make gene therapy an appealing solution that addresses the root cause of the problem. The primary aims of the NIH-funded effort are to ensure that gene editing does not have unintended side effects that do more harm than good. To do this, the team will screen different gene therapies for their effects on normal kidney function and the risk of renal cancer or autoimmune disease.
“Our hypothesis is that gene editing will cause adverse effects, but that these effects are predictable and controllable,” says Freedman. “Our goal is to prove this using laboratory models like organoids and kidneys on chips so we know the approach is safe before we ever involve a human patient.”
Joining Freedman on the UW research team are ISCRM colleagues Hannele Ruohola-Baker PhD, a Professor in Biochemistry, and Julie Mathieu PhD, an Assistant Professor in Comparative Medicine. Ruohola-Baker will investigate how genome-editing therapies affect metabolism in the cells. Mathieu adds CRISPR expertise to the UW research team. Several additional faculty members from ISCRM and other departments are also on the team.
How broad are the implications of developing responsible genome-editing methods? “This is a new paradigm for therapy development,” says Freedman. “We’re looking at the kidney. But the liver, heart, and lungs all have similar challenges. Our hope is to create a model for doing this work in human organoids, which are faster and more humane than animal models, and can be more directly compared to human patients.”