Researchers at Mayo Clinic have developed a base editing therapy for autosomal dominant polycystic kidney disease (ADPKD), a genetic condition affecting one in 1,000 people. Their findings, published recently in Nature Communications, set a new precedent for treating genetic conditions affecting the kidneys, which have historically proven difficult to target with gene editing technologies.
“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,” says Xiaogang Li, PhD, 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.”
ADPKD is caused by mutations in the PKD1 or PKD2 genes that lead to the slow growth of cysts in the kidneys, starting during fetal development and continuing throughout life. By the time they reach 60 years of age, 60% of ADPKD patients will have developed kidney failure, and complications affecting the heart and liver are also common. Currently, only one FDA-approved drug is available for this condition, and the treatment only delays the appearance of some symptoms while often causing serious side effects.
Point mutations are the most common genetic variants causing ADPKD, making base editing a promising approach to more effectively treat this condition. Li and colleagues engineered two versions of a CRISPR-Cas9 base editor to correct a single-nucleotide DNA mutation in the PKD1 gene with minimal off-target effects. One version was designed to work across the entire body while the other was targeted uniquely to the kidney.
In a mouse model of ADPKD, a single dose of the treatment was able to correct the mutation in a significant proportion of kidney cells, with both versions reducing the growth of kidney cysts and extending survival. While the kidney-specific version proved better at editing point mutations in the kidneys, the universal base editor also corrected the target mutation in heart and liver cells, reducing heart enlargement symptoms and improving liver health.
“Being able to precisely control where editing happens is critical,” says Li. “It allows us to maximize benefit while minimizing risk.”
The structural and functional complexity of the kidneys has long posed a challenge for the effective delivery of CRISPR-based therapies. In their study, Li and colleagues achieved unprecedented results using adeno-associated viruses (AAVs) as a delivery vector, which are known for their safety, low immunogenicity, and ability to provide long-lasting gene expression of at least six months with a single dose.
The success of this approach opens the door for similar approaches to target a wide range of inherited kidney diseases. As part of future development work, the researchers aim to test alternative delivery methods such as lipid nanoparticles, evaluating the efficacy of the treatment after cysts have formed, and developing a range of base editors that address multiple PKD gene mutations.
“Our results suggest this could one day be a treatment that meaningfully changes the course of disease,” says Li. “That is fundamentally different from lifelong therapies that only slow progression. 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.”
