New modeling system identifies potential treatments for autosomal recessive polycystic kidney disease

Organoids; cells or tissues grown in the laboratory that look like organs; serve as a new tool for disease modeling, but researchers often struggle to replicate the biophysical conditions under which organs function in the body.

This is especially true for modeling human diseases that require stimuli from cellular microenvironments.

A research team from Massachusetts General Hospital, Brigham and Women’s Hospital, Wyss Institute and colleagues recently united organoids with organ-on-a-chip technology to replicate the unique disease process underlying autosomal recessive polycystic kidney disease (APRKD).

In a recent study in Scientists progressThe team, led by Ken Hiratsuka, MD, PhD, and Ryuji Morizane, MD, PhD, reports the use of the new modeling system to identify two potential therapies for APRKD, which currently has no treatment approved by the FDA.

APRKD is a disorder characterized by the formation of cysts in the kidneys, which enlarge the organs and cause the gradual loss of kidney function. It reported a mortality rate as high as 30% in infancy. Of those who survive, 41% will need a kidney transplant before age 11.

The gene responsible for the disease is PKHD1, but previous attempts to model the disease in genetically modified mouse models have failed.

The researchers were able to grow mutated PKHD1 cells in the lab. However, modeling the disease in a static 3D organoid does not work because it is caused by a cell surface mutation that is stimulated by urinary flow.

To overcome this challenge, the team used a 3D printer to create a perfusion chip that models the microenvironment of cells in the kidney and allows fluid to flow through the organoids.

In doing so, the team identified two mechanosensitive molecules (FOS and RAC1) that are potential therapeutic targets for the disease.

They also shed light on two important questions regarding the pathological mechanisms of ARPKD:

  • That the FOS molecule may be a crucial species-specific deterrent to cyst formation, which is why mouse models have failed to effectively replicate the disease
  • Why mutations in the PKHD1 gene lead to the formation of cysts

The team also tested two FDA-approved drugs (R-Naproxen and R-Ketorolact) that inhibit RAC-1 and an experimental new drug that inhibits FOS (T-5224), all of which were found to have positive effects. therapies in these models.

Clinical trials will now be needed to study these therapies in patients with ARPKD. The success of the organoid modeling system in disease replication could also help researchers identify more potential treatment targets.

In this study, we showed that our kidney organoids on a chip platform provide a physiologically relevant model for ARPKD, allowing the identification of mechanodetection signals as key drivers of cystogenesis.

Ryuji Morizane, Research Fellow, Division of Neurology at Mass General and Assistant Professor of Medicine, Harvard Medical School

“To validate our findings, FDA-approved NSAIDs that inhibit RAC1 along with a clinically tested FOS inhibitor were shown to have therapeutic effects in our model. Our observations highlight the vast potential of organoid models on-chip to elucidate complex mechanisms of disease for therapeutic testing and discovery.

Funding for the study was provided by the National Institutes of Health, a research fellowship from the Uehara Memorial Foundation, and a start-up grant from the Harvard Stem Cell Institute.


Massachusetts General Hospital

Journal reference:

Hiratsuka, K. et al. (2022) Organoid-on-chip model of human ARPKD reveals mechanodetection pathomechanisms for drug discovery. Scientists progress.

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