A single-dose gene-editing therapy has shown it can correct the genetic cause of autosomal dominant polycystic kidney disease in preclinical models, slowing cyst growth, improving organ health and potentially leading to future treatments that target the disease at its source.

Researchers at Mayo Clinic have developed a gene-editing therapy that directly corrects the genetic mutation responsible for autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder. The experimental treatment, delivered as a single dose, slowed the growth of kidney cysts, improved heart and liver health and extended survival in preclinical models.

ADPKD affects an estimated 12 million people worldwide and is primarily caused by mutations in the PKD1 or PKD2 genes. The condition leads to the progressive growth of fluid-filled cysts in the kidneys and often results in kidney failure. Many patients also develop complications beyond the kidneys, including heart enlargement and liver disease.

Targeting the genetic root

Current treatments for ADPKD can slow disease progression but do not address its underlying genetic cause. The new approach uses a CRISPR-based technology known as base editing to precisely correct a single-letter DNA mutation in the PKD1 gene.

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The new approach uses a CRISPR-based technology known as base editing to precisely correct a single-letter DNA mutation in the PKD1 gene.

“This is the first time we’ve been able to show that base editing can effectively and safely correct a disease-causing mutation in the kidney in a complex biological system,” said Dr Xiaogang Li, a nephrology researcher at Mayo Clinic and senior author of the study. “Instead of managing symptoms, this strategy goes after the underlying cause of the disease.”

To test the approach, the researchers engineered two versions of a base editor. One was designed to work broadly across multiple organs while the other was tailored specifically to kidney cells. Both were delivered using adeno-associated virus vectors.

Promising preclinical results

A single treatment corrected the PKD1 mutation in a significant proportion of kidney cells and, depending on the editor used, in the heart and liver as well. When preclinical models were treated early in life, they showed markedly reduced kidney cyst growth, better kidney function, less heart enlargement, improved liver health and longer survival.

Importantly, the team found no evidence of harmful off-target genetic changes or significant immune reactions, a key consideration for the future safety of gene-editing therapies.

“Our results suggest this could one day be a treatment that meaningfully changes the course of disease,” Dr Li said. “That is fundamentally different from lifelong therapies that only slow progression.”

Overcoming a difficult target

The kidney has been notoriously difficult to reach with gene-editing therapies. This study provides the first in vivo evidence that base editing can work 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 work efficiently in kidney tissue.

The researchers also showed that kidney-specific gene editing can confine genetic changes to the intended organ, a feature that could enhance safety as treatments move closer to human testing.

“Being able to precisely control where editing happens is critical,” said Dr Li. “It allows us to maximise benefit while minimising risk.”

Looking ahead

The work supports Mayo Clinic’s Genesis initiative, which focuses on preventing organ failure and restoring function through regenerative medicine, precision genomics and advanced therapies. Ongoing studies are refining base-editing tools to address a wider range of PKD mutations, testing whether treatment remains effective after cysts have formed and exploring alternative delivery methods, including nonviral options like nanoparticles.

“If these approaches translate successfully to humans, they could reduce or even eliminate the need for chronic medication, delay kidney failure and significantly improve quality of life for patients with ADPKD,” Dr Li concluded.