Researchers Uncover Novel Method to Increase Key Polycystic Kidney Protein

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure. Despite decades of research, treatment options for the disease remain limited, and many patients ultimately require dialysis or kidney transplantation.

Now, researchers at Yale have identified a potential new strategy for treating the disease. In a study recently published in The Journal of Clinical Investigation, the team discovered a novel way to increase production of polycystin-1, a protein that is deficient in most cases of ADPKD.

The disease is characterized by fluid-filled cysts that gradually enlarge and replace healthy kidney tissue, leading to a progressive decline in kidney function, explains Whitney Besse, MD, assistant professor of medicine (nephrology) at Yale School of Medicine and senior author of the study.

In most patients, ADPKD is caused by genetic mutations that reduce the amount of functional polycystin-1 available to the kidney. Previous research has shown that even modest increases in polycystin-1 levels could have therapeutic benefits and reduce cyst formation, making ways to boost its production a longstanding goal for researchers studying the disease, Besse says.

The strategy explored in the study was inspired by a seminar Besse attended several years ago as part of a Yale Rare Disease Seminar Series. There, a Yale graduate student introduced her to upstream open reading frames, or uORFs, short stretches of genetic code located before the main protein-coding portion of a gene.

Prior to that talk, I'd never heard of uORFs. But I learned that when a gene has active upstream open reading frames, the cell may be less efficient at producing the protein that gene is meant to produce. This caught my attention because polycystin-1 protein levels have always seemed lower than expected."

Whitney Besse, Assistant Professor of Medicine (nephrology), Yale School of Medicine

The presentation prompted Besse to wonder whether uORFs might be placing an additional limit on polycystin-1 production in patients with ADPKD. Blocking these sequences, she reasoned, could allow cells to produce more of the protein and potentially offer a new approach to treating the disease. Publicly available data also supported the hypothesis that the gene for polycystin-1 was highly likely to have active uORFs.

To test the idea, Besse and her team developed in vitro models and ultimately made genetically engineered mouse models to examine how uORFs affect polycystin-1 production. They found that disrupting the uORFs increased polycystin-1 levels by approximately two- to four-fold in vitro and in vivo. Importantly, this increase prevented kidney cysts from developing in mice predisposed to polycystic kidney disease.

"These models allowed us to show that small upstream open reading frames act as a translational brake on polycystin-1 production, and that releasing this brake can meaningfully change disease outcomes in vivo." says Zhigui Li, PhD, an associate research scientist in Besse's lab and first author of the study.

The findings point to a different way of thinking about genetic therapies, says Besse. "Many genetic therapies knock down or knock out a gene to decrease protein production, but for genes with active uORFs, blocking them is an approach that can increase the expression of a gene," she says. For ADPKD, where even modest increases in polycystin-1 may be beneficial, that distinction could be particularly important.

The team's next steps include identifying which patients may be most likely to benefit from the approach, including whether certain genetic mutations make patients better candidates for treatment. The researchers are also working to optimize therapies that can block uORFs and effectively reach the kidneys.

"We find that RNA-like genetic therapies called antisense oligonucleotides (ASOs) can block uORFs to increase polycystin-1 expression in cells, so we are now working on testing these and similar approaches in mice," Li adds.

The discovery has also received support from Yale Ventures, which helped Besse and her team patent the approach as they work toward translating the findings into a potential therapy.

Besse hopes the findings will eventually lead to new treatment options for patients and families affected by ADPKD.

"There are many patients and families who I have cared for in clinical settings and/or enrolled into our genetic research studies that motivate me," Besse says. "This is a disease that can have such a profound effect on families, and I look forward to the day when we can offer more."

Nephrology is one of 10 sections in the Yale Department of Internal Medicine. Committed to excellence in patient care, research, and education, the section's faculty and trainees aim to be national and international leaders in academic nephrology. To learn more, visit Nephrology.