Polycystic kidney disease (PKD) is a hereditary condition characterized by the formation of fluid-filled cysts in the kidneys. These cysts can grow uncontrollably, leading to significant pain and reduced kidney function, often resulting in the need for dialysis in severe cases. Currently, there is no definitive cure for PKD. However, a team of researchers at UC Santa Barbara has proposed a novel cyst-targeted therapy that aims to halt the growth of these cysts using a specific type of monoclonal antibody.
The study, led by Thomas Weimbs, a biologist at UCSB, was published in the journal Cell Reports Medicine. Weimbs emphasized the urgency of the situation, stating, “The cysts just keep growing endlessly. And we want to stop them.” The team is focused on delivering a drug directly into the cysts, where it can effectively disrupt their growth.
Existing treatments include various small-molecule drugs that can moderate cyst growth, but these are often accompanied by significant side effects and toxicity to surrounding kidney tissues. According to Weimbs, the only available drug that shows some effectiveness in slowing disease progression has limited applicability due to its adverse effects. The research team identified lab-grown therapeutic antibodies as a potential alternative, but the commonly used immunoglobulin G (IgG) antibodies are too large to penetrate the cysts.
Weimbs explained, “IgG antibodies never cross the cell layers and they can never make it inside the cysts.” Inside the cysts, cells release growth factors that can perpetuate their own activation and contribute to cyst expansion. To effectively target these processes, the researchers turned to a specialized antibody known as dimeric immunoglobulin A (dIgA). This antibody is capable of crossing epithelial membranes, allowing it access to the cysts where it can address the root cause of their growth.
The team previously outlined this approach in a 2015 paper, highlighting that dIgA binds to polymeric immunoglobulin receptors on epithelial cells, facilitating its entry into the cysts. In their recent study, the researchers engineered the dIgA antibody to target the cMET receptor, which plays a crucial role in driving cyst progression. After altering the DNA sequence of the IgG, the team confirmed that the newly developed dIgA could effectively bind to the cMET receptor.
The researchers then tested the engineered antibody in mouse models of PKD. They observed that the dIgA successfully penetrated the cysts and inhibited cMET activity, leading to a reduction in cell growth signals. Significantly, the treatment also induced a “dramatic onset of apoptosis” in cyst epithelial cells, while leaving healthy renal tissue unaffected.
Despite these encouraging results, Weimbs cautioned that the research remains in preclinical stages. “It will be quite a while before this treatment done to mice can be transferred to human beings,” he noted. Future steps include the search for potential partners interested in PKD research and access to advanced facilities for antibody development.
The researchers aim to explore additional growth factors that may be involved in cyst fluid dynamics. Weimbs remarked, “In the literature, there are dozens of growth factors that have been shown to be active in these cyst fluids.” The team plans to compare the effectiveness of blocking various growth factors and receptors, potentially combining different antibodies for maximum therapeutic impact.
This research, spearheaded by Margaret F. Schimmel and supported by colleagues including Bryan C. Bourgeois, Alison K. Spindt, Sage A. Patel, Tiffany Chin, Gavin E. Cornick, and Yuqi Lu, represents a significant step forward in the quest for effective treatments for PKD. For more detailed findings, refer to the published study: Margaret F. Schimmel et al, Development of a cyst-targeted therapy for polycystic kidney disease using an antagonistic dimeric IgA monoclonal antibody against cMET, Cell Reports Medicine (2025).
