A single-dose gene editing therapy has shown in preclinical models that it can correct the genetic cause of autosomal dominant polycystic kidney disease, slow cyst growth and improve organ health, potentially leading to future treatments targeting the cause of the disease.
researchers mayo clinic developed gene editing Treatments that directly correct the genetic mutations that cause autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease. This experimental treatment, administered as a single dose, slowed the growth of kidney cysts, improved heart and liver health, and prolonged survival in preclinical models.
ADPKD affects an estimated 12 million people worldwide and is primarily caused by mutations in the PKD1 or PKD2 genes. This condition causes the progressive growth of fluid-filled cysts within the kidneys, often leading to kidney failure. Many patients also develop non-kidney complications, such as an enlarged heart and liver disease.
Targeting the genetic roots
Current treatments for ADPKD can slow the progression of the disease, but do not address its underlying genetic causes. The new approach uses a CRISPR-based technology known as base editing to precisely correct single-letter DNA mutations in the PKD1 gene.
The new approach uses a CRISPR-based technology known as base editing to precisely correct single-letter DNA mutations in the PKD1 gene.
“This is the first time that we have been able to show that base editing can effectively and safely correct disease-causing mutations in the kidney in a complex biological system,” said Dr. Xiaogang Li, a Mayo Clinic nephrology researcher and senior author of the study. “This strategy seeks the root cause of the disease rather than managing symptoms.”
To test this approach, the researchers designed two versions of the basic editor. One is designed to function broadly in multiple organs, and the other is tailored specifically to kidney cells. Both were delivered using adeno-associated virus vectors.
Promising preclinical results
A single treatment corrected PKD1 mutations in a significant proportion of kidney cells and, depending on the editor used, in the heart and liver as well. Preclinical models were shown to significantly reduce renal cyst growth, improve renal function, reduce cardiac hypertrophy, improve liver health, and extend survival when treated early in life.
Importantly, the team found no evidence of deleterious off-target genetic changes or significant immune responses, important considerations for the future safety of gene-editing therapies.
“Our results suggest that this could one day be a treatment that significantly changes the course of the disease,” Dr. Lee said. “That’s fundamentally different from lifelong treatment, which only slows progression.”
overcome difficult goals
The kidney is notoriously difficult to access with gene editing therapies. This study provides the first in vivo Base editing has been shown to function efficiently in kidney tissue, which could lead to similar strategies for other inherited kidney diseases.
This study provides the first in vivo Evidence that base editing can function efficiently in kidney tissue.
The researchers also showed that kidney-specific gene editing allows genetic changes to be localized to the organ of interest, a feature that could make treatments safer as they move closer to human testing.
“It’s important to be able to control exactly where the edits occur,” says Dr. Lee. “This allows us to maximize profits while minimizing risk.”
Looking to the future
This work supports Mayo Clinic’s Genesis Initiative, which focuses on preventing organ failure and restoring function through regenerative medicine, precision genomics, and advanced treatments. Ongoing research is refining base editing tools to address a wider range of PKD mutations, testing whether therapeutic effects persist after cyst formation, and exploring alternative delivery methods, including non-viral options such as nanoparticles.
“If these approaches can be successfully translated to humans, the need for chronic medications could be reduced or even eliminated, potentially delaying kidney failure and significantly improving the quality of life for ADPKD patients,” Dr. Lee concluded.