Gene-Editing Innovations in Kidney Disease Treatment: A New Era

Researchers reported preclinical evidence that CRISPR base editing can directly correct a pathogenic single-nucleotide mutation in the PKD1 gene, addressing the underlying genetic cause of autosomal dominant polycystic kidney disease (ADPKD).

The experimental therapy was delivered as a single dose and is presented as a potential disease-modifying approach, although it remains at a preclinical stage. The strategy uses base-editing technology rather than double-strand DNA cleavage to install a precise single-base correction in vivo. To test the approach, investigators engineered two versions of a base editor: one designed for broader activity across multiple organs and another tailored to kidney cells. Both editors were delivered using adeno-associated virus (AAV) vectors, enabling in vivo correction of the PKD1 mutation in kidney tissue and, depending on the editor used, in heart and liver as well.

In preclinical models treated early in life, a single administration resulted in a significant proportion of kidney cells carrying the corrected PKD1 sequence. Treated models showed markedly reduced kidney cyst growth, improved measures of kidney function, less heart enlargement, improved liver health, and extended survival compared with untreated controls. These findings indicate that directly correcting the disease-causing mutation can alter the course of disease in multiple affected organs.

Importantly, the researchers reported no evidence of harmful off-target genetic changes or significant immune reactions in the assays performed, supporting the potential safety of the base-editing approach in these preclinical studies. The work also provides the first in vivo evidence that base editing can be achieved efficiently in kidney tissue, a target that has historically been difficult to reach with gene-editing technologies.

The authors note that refining base-editing tools to address a broader range of PKD mutations, testing efficacy after cysts have already formed, and exploring alternative delivery strategies are ongoing areas of investigation. If these approaches ultimately translate to humans, they could represent a shift from lifelong symptom-modifying therapy toward a single-dose intervention that directly addresses the genetic root of ADPKD.