Polycystic kidney disease (PKD) is a hereditary condition characterized by the formation of fluid-filled cysts in the kidneys. As these cysts grow, they can severely impair kidney function, often resulting in the need for dialysis in severe cases. Currently, no cure exists for PKD. However, researchers at UC Santa Barbara have proposed a novel therapy aimed at targeting the cysts and potentially halting their growth by utilizing specific monoclonal antibodies designed for this purpose.
The study, led by Thomas Weimbs, a biologist at UC Santa Barbara, was published in the journal Cell Reports Medicine. Weimbs emphasized the urgency of this research, stating, “The cysts just keep growing endlessly. And we want to stop them. So we need to get a drug into these cysts that will make them stop.” Traditional treatments for PKD have been limited, with only one approved drug offering some effectiveness, yet it carries significant side effects and toxicity risks to surrounding kidney tissues.
To address these challenges, the research team focused on using lab-grown therapeutic antibodies. Conventional immunoglobulin G (IgG) antibodies, commonly used in cancer therapies, 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.” This limitation highlights the need for a different approach to effectively deliver treatment directly to the cysts.
The researchers turned their attention to a different type of antibody, known as dimeric immunoglobulin A (dIgA). This immune protein, which naturally occurs in saliva, tears, and mucus, has the unique ability to cross epithelial membranes. By binding to polymeric immunoglobulin receptors on epithelial cells, dIgA can be transported into kidney cysts, where it can target specific receptors responsible for cyst growth.
The study builds on previous findings from a 2015 paper, demonstrating the therapeutic potential of dIgA by targeting the cMET receptor, a key driver in cyst progression. The research team engineered an antibody protein by modifying the DNA sequence of IgG, creating a dIgA antibody. They then tested the efficacy of this engineered antibody in mouse models, confirming its ability to penetrate cysts and inhibit the cMET receptor.
Results from these experiments indicated that the dIgA treatment successfully blocked cMET activity, reducing cell growth signals. Furthermore, the treatment prompted significant apoptosis, or cell death, in cyst epithelial cells without adversely affecting healthy kidney tissues. This finding represents a crucial step forward in developing a targeted therapy for PKD.
Despite these promising results, the research is still in the preclinical stages. Weimbs noted that transitioning this treatment from animal models to human applications will take time. Future challenges include securing partnerships with organizations interested in PKD, as well as gaining access to facilities capable of producing the required antibodies.
“We can also combine different antibodies against different receptors at the same time. That would be the next step,” Weimbs stated. The team plans to explore various growth factors active in cyst fluids to identify the most effective treatment approaches.
The collaborative effort behind this research also includes lead author Margaret F. Schimmel and fellow researchers Bryan C. Bourgeois, Alison K. Spindt, Sage A. Patel, Tiffany Chin, Gavin E. Cornick, and Yuqi Lu, all part of the team at UC Santa Barbara.
As the project progresses, the potential for a breakthrough therapy for PKD offers hope to patients living with this challenging condition. Further studies and clinical trials will be necessary to establish the safety and effectiveness of this innovative treatment strategy.
