New Modeling System May Advance Care for Autosomal Recessive Polycystic Kidney Disease


Innovative system reveals a pair of potential therapies for autosomal recessive polycystic kidney disease, which currently has no FDA-approved treatments.

An innovative new modeling system may advance the care of patients with autosomal recessive polycystic kidney disease (APRKD), according to a study published in Science Advances.

Investigators from Massachusetts General Hospital, Brigham and Women’s Hospital, and the Wyss Institute were able to combine organoids with organ-on-a-chip technology to mirror the disease process beneath APRKD. Organoids are lab grown cells or tissues that are similar to organs. However, prior research efforts in this area created challenges in replicating the biophysical conditions in which the organs operate in the human body, especially in modeling diseases that need stimuli from cell microenvironments, according to the study.

The investigative team, led by Ken Hiratsuka, MD, PhD, and Ryuji Morizane, MD, PhD, found that the new modeling system identified a pair of potential therapies for APRKD, which currently has no treatments that have been approved by the FDA.

“In this study, we showed that our kidney organoids on a chip platform provides a physiologically relevant model for ARPKD, allowing the identification of mechanosensing signals as key drivers of cystogenesis,” Morizane said in a press release.

In APRKD, cysts develop in the kidneys, which causes the organ to enlarge and leads to the progressive loss of renal function. APRKD has a mortality rate up to 30% in infancy, while 41% of patients who survive need kidney transplantation by 11 years of age, according to the study.

PKHD1 is causative gene for APRKD, however, prior efforts to model the disease in genetically modified mice were unsuccessful. In the current study, the investigators were able to cultivate mutated PKHD1 cells in the lab. However, they were unable to model the disease in a static 3D organoid because it is caused by a mutation on the surface of the cells stimulated by urinary flow, the study authors wrote.

To address this issue, the investigators used a 3D printer to produce a perfusion chip that mimics the microenvironment of cells in the kidney, permitting liquid to flow through the organoids.

In doing this, the investigators identified a pair of mechanosensing molecules, FOS and RAC1, which were found to be potential therapeutic targets for ARPKD. The study also found 2 vital questions in the disease mechanisms of ARPKD.

First, they found that FOS may be a crucial determent of species-specific cyst formation. This may explain why research efforts have been unable to effectively replicate ARPKD in mouse models. Secondly, they may have found why mutations in the PKHD1 gene cause cysts to develop.

The researchers tested 2 FDA-approved drugs, R-Naproxen and R-Ketorolact, that inhibit RAC-1, as well as an investigational new drug, T-5224, which inhibits FOS. These treatments were found to have therapeutic efficacy in these models, according to the study.

The researchers said that clinical trials will now be required to evaluate the drugs in patients with ARPKD. The modeling system may also enable additional studies to identify more potential treatment targets.

“In validation of our findings, FDA-approved NSAIDS that inhibit RAC1 as well as a clinically tested inhibitor of FOS are shown to have therapeutic effects in our model. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery,” Morizane added.


Hiratsuka, K., Miyoshi, T., Kroll, K., Gupta, N., Valerius, M., Ferrante, T., Yamashita, M., Lewis, J. and Morizane, R., 2022. Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery. Science Advances, 8(38). Accessed September 23, 2022.

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