Polycystic Kidney Disease In Vitro Center (PKD-InVent)

About This Grant

The overall goal of this project is to expand and enable the preclinical-to-clinical research pathway for  polycystic kidney disease (PKD) by generating products, services, and education focusing on human PKD organoids and related cellular systems, via a PKD In Vitro Center (PKD-InVent) dedicated to this area.  PKD is commonly inherited as a loss-of-function mutation in PC1 (polycystin-1) or PC2, which form a membrane complex. Thirty years after its discovery, the function of this complex remains enigmatic. A major roadblock has been the lack of assays that re-create PKD in vitro. Mice are highly complex, low-throughput, and non-human, whereas simple cells lack a PKD-specific phenotype.  Ten years ago, we reported a breakthrough - a human organoid model of PKD that expresses the pathognomonic phenotype of cyst formation. PKD1-/- and PKD2-/- organoids, derived from human stem cells, recapitulated the pathognomonic cystic phenotype in a PKD-specific manner. This revealed that PKD, previously believed to require factors found exclusively in vivo, is actually a cell intrinsic process.  PKD organoids have revealed surprising mechanisms, new candidate drugs, and public attention. We have helped other labs reproduce our discoveries, including current members of the PKD RRC. But the potential of organoids is not yet realized. The complexity and cost of organoid disease modeling remain significant barriers to entry, and there remain clear challenges for PKD organoids that require dedicated technology development. PKD-InVent will create a new center within the PKD RRC, drawing in new investigators and increasing innovation. It will make available the world’s largest collection of PKD and ciliopathy iPS cells, with protocols for organoid differentiation, phenotyping, and analysis. The experts in the field will devote time and effort to providing products, services, and training experiences, for which there is already strong demand. Focusing on organoids will bequeath this technology the attention it needs, and save the RRC time re-inventing the wheel. This will enable the technology to flourish and scale, so that it can reach its potential.  The University of Washington is extremely well-positioned to accomplish this vision. Our world-renowned team will connect the PKD RRC with other NIH Consortia, including an FDA partnership to qualify PKD organoids as clinically relevant biomarkers. Our team has a strong track record of providing high-quality reagents and data, expertise in PKD and cell biology, and knowledge of pain points. Our Center will equip and train the field for PKD organoid research, even as it further improves the technology to address unmet needs. We will accomplish this via four Specific Aims: (1) Create and organize an integrated Center for modeling PKD in vitro. (2) Maximize potential of existing organoid technology by equipping and educating the research community. (3) Expand and improve PKD in vitro models through multidisciplinary innovation.