Published on October 19, 2021 |  As a genetic disease, ADPKD (autosomal dominant polycystic kidney disease) is caused by mutations in either the PKD1 or PKD2 gene. These genes encode the proteins polycystin-1 and polycystin-2, respectively, which together form the polycystin complex. When there’s a reduction or complete loss of polycystin function, this leads to cyst growth in PKD. While we know that loss of polycystin function leads to ADPKD, ADPKD research hasn’t answered if restoring polycystin function impacts the progression of ADPKD. In a recent study, scientists sought to answer one key question. How does restoring polycystin function impact the progression of ADPKD in mouse models? So far, they’ve seen positive results in reversing ADPKD in mice.

ADPKD Research Mice Models Study

This work was in part funded by a PKDF Investigator Grant in 2014 to Ming Ma, Ph.D., which explored the effects of genetic reactivation of polycystins on the progression of PKD. We are also delighted to have funded Dr. Somlo’s team’s research for many years. In this study, they discovered restoring polycystin function not only slows but reverses ADPKD in this mouse model of disease. That’s incredibly exciting news! This finding is surprising in the capacity of the kidney for plasticity (ability to change), and that this plasticity is in part controlled by the ADPKD genes. Importantly, this work provides a strong rationale for therapeutic approaches to ADPKD aimed at restoring polycystin function.

PKD kidney

Restoring Polycystin Function Early in Progression

To answer the key question, scientists created genetically engineered mice in which the PKD1 or PKD2 gene could be turned off to kickstart the disease and then turned back on. This allowed them to thoroughly evaluate the impact of restoring polycystin function on the progress of ADPKD, both in early and later stages of the disease. Restoring polycystin function early in animals with ADPKD not only slowed disease progression but actually reversed the diseased state. Kidney cysts were largely eliminated, kidney size returned to normal, kidney anatomy and function were restored. Also, overall, kidneys in experimental animals were similar to control animals (in which ADPKD was not induced by kickstarted at all). Other important aspects of ADPKD, including markers of inflammation and fibrosis (tissue damage, scarring), were also reversed with reactivation of polycystin function.

Restoring Polycystin Function Late in Progression

Restoring polycystin later in animals with ADPKD reversed progression of the disease as well. Although, to a lesser degree. As in animals in which polycystin reactivation was performed earlier in disease, cysts were largely eliminated, and kidney size and structure returned to normal. However, inflammation and markers of fibrosis were only partially returned to normal. But this isn’t surprising. Inflammation, and particularly fibrosis, represent damage to the kidneys caused by cyst growth and subsequent damage to the kidney. This damage wouldn’t be expected to be fully reversed when the cysts go away.

Overall, findings provide hope that restoring polycystin function, or “reparative remodeling,” is a viable approach to treating ADPKD. Additionally, results demonstrate the potential to intervene even late in the disease to reverse ADPKD progression. This suggests a wide window of opportunity to intervene—which is ideal.

Understanding the Function of Polycystin

The loss of polycystin not only plays a role in cyst formation and growth but also in the inflammatory and fibrotic aspects of the PKD. This study confirms polycystins play a key role in maintaining and regulating the healthy structure and organization of the kidney. We still don’t fully understand the molecular function of the polycystin complex, but this research provides key insights into the role of polycystin in kidney structure and organization—shaping future research efforts into understanding the molecular function of the polycystins.

Study Limitations

Though this news is exciting, it’s important to remember that findings in mice aren’t directly applicable to treating disease in people. The genetic model used in this study with mice is different than how ADPKD presents in humans. For humans, the genetic cause of ADPKD is heterogeneous, meaning individuals have a wide range of mutations in ADPKD genes. This mouse model is homogenous in both the genetic cause of disease and the timing of polycystin loss. This isn’t the case in humans, and so the results observed in this study are an ideal case.

Reactivation of polycystin function is also homogenous, greater than natural polycystin expression, and occurs in almost all disease cells. Interventions in humans wouldn’t be expected to intervene in all disease cells. That means observations in this model represent a best-case scenario. The most similar approach to treat ADPKD in humans would be add-back gene therapy. However, the PKD1 and PKD2 genes are too large to be delivered by traditional gene therapy. So, this approach currently isn’t a feasible therapy in people either.

For now, it’s not clear how directly translatable these findings are to people with ADPKD.

Advancing ADPKD Research for Potential Therapeutic Treatments

What is the right approach to restore polycystin function in people with ADPKD? In order to answer that question, the PKD Foundation is funding multiple approaches, providing a strong portfolio of projects aimed at restoring polycystin function as a treatment for PKD. A primary function of our grants program is to fund innovative, early research to identify potential therapeutic treatments for PKD that then goes on to apply for larger NIH-funded grants.

Over the past several years, the Foundation funded multiple scientists to evaluate a variety of approaches to restore polycystin function. These grants included:

2020 Fellowship, Laura Onuchic, M.D.: This project is a gene therapy approach. A gene encoding a portion of polycystin-1 is introduced into kidneys to restore polycystin function.

2020 Investigator Grant, Stephen Parnell, Ph.D.: This project explores the use of a small portion of polycystin-1 as a peptide drug to restore polycystin function.

2021 Fellowship, Alysia Cox, Ph.D.: This project investigates restoring polycystin function by using targeted delivery of mRNA encoding polycystin-2 to the kidneys. This mRNA technology is similar to what’s used in the Pfizer and Moderna COVID vaccines.

2021 Fellowship, Cynthia Sieben, Ph.D.: This project is exploring the use of small molecules drugs that help restore the function of mutated polycystin proteins (known as chaperone therapy) to increase polycystin function.

We believe that together, these four approaches provide a broad set of independent therapeutic approaches to making restoring polycystin function a treatment for ADPKD. The future of ADPKD research is exciting and full of hope for new therapeutic treatments. To that end, our $70 million Future Focus campaign—the most ambitious in our 40-year history—aims to increase our research commitment by 300%. Since its launch five years ago we’ve already increased research grant funding by 230%, funding 56 researchers in the past four years alone. Through this campaign and our support of researchers like Dr. Somlo, we continue to usher in new hope in the fight to #endPKD.

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