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As good as the real thing?
SAN DIEGO—Organovo Holdings Inc., a 3D biology company, has announced the publication of data in Frontiers in Physiology showing that its 3D bioprinted proximal tubule tissue model exhibits key characteristics of renal physiology that allow for in-vitro kidney toxicity testing. In addition, Organovo noted a recent article published in the ILAR Journal. The publication explored new technologies that could reduce both dependency on animal models and occurrence of liver toxicity in clinical trials, and provides a thorough review of human tissue models and how they can accelerate drug development across all discovery stages, including Organovo’s 3D bioprinted liver model.
“Both liver and kidney drug toxicities are significant challenges for pharmaceutical companies working to advance safe and effective therapeutics,” said Keith Murphy, CEO of Organovo. “Previous validation data of our 3D bioprinted human liver tissue, combined with the data published in the peer-reviewed journal Frontiers of Physiology, on our 3D bioprinted kidney proximal tubule tissue clearly show that Organovo’s technology can address the unmet needs of our pharma customers and partners by providing timely, cost-effective and more accurate human tissue models for evaluating drug toxicity and drug-induced fibrotic disease.”
According to Dr. Deborah Nguyen, senior director of research and development at Organovo, “The ExVive 3D Bioprinted Liver Tissue was commercially launched in 2014 and has demonstrated its potential to assess drug-related injury and fibrosis. The ExVive 3D Bioprinted Kidney Tissue was commercially launched in 2016. Organovo’s bioprinted kidney tissues provide a more accurate and reproducible model of human proximal tubule biology, enabling the investigation of multiple mechanisms of nephrotoxicity as well as renal disease.”
“Bioprinting is an automated process that places cells and cell-containing materials in precise locations in three-dimensional space so the cells naturally take on the shape and structure of native human tissue,” adds Nguyen. She says this 3D arrangement is achieved by generating multicellular building blocks—bio-ink—from the cells that will be used to build the target tissue. “[With] kidney tissue, three renal cell types are used to reconstruct the proximal tubule portion of the nephron. Those cell types are renal fibroblasts, endothelial cells and polarized human renal proximal tubule epithelial cells. The bio-ink building blocks are dispensed from a bioprinter, using a layer-by-layer approach, very similar to building a model with LEGO blocks.”
Asked about the differences in traditional toxicity testing vs. this new model, Nguyen tells DDNews, “Traditional toxicity testing generally consists of 2D cell culture models and animal models. Both of these methods fall short of being able to accurately predict the toxic effect any one drug will have once it reaches clinical trials. In the case of the kidney, 2D cell culture can be limiting because the models typically consist of epithelial cells alone in a single layer, which does not provide understanding of the complex cell-cell interactions that take place in the native kidney. They miss some of the mechanisms of kidney injury such as fibrosis, which is mediated by renal fibroblasts. Many traditional 2D kidney cell culture models use immortalized cell lines, and these cancer cells often have different functions compared to normal human primary cells. In addition, the more physiologic primary 2D cell culture models typically lose native function rapidly and therefore cannot be tested for more than a few days.”
Organovo’s kidney tissue provides architecture and multiple cell types that more fully recapitulate the human proximal tubule and allows for analysis of compounds for at least two weeks, according to Nguyen. “With animal models, it comes down to the fact that there are inherent differences between these models and humans that lead to an inability to fully predict clinical outcomes. Organovo’s bioprinted kidney tissue is fully human, eliminating any differences between species.”
She says Organovo is continuing to work internally and with customers to apply the ExVive 3D Bioprinted Kidney Tissue model in preclinical testing to improve safety and reduce time to market for new therapeutics, adding: “There are many compounds that induce acute kidney injury which are not appropriately identified during preclinical testing. Our kidney tissues provide a solution, allowing researchers to easily test their compounds in a fully human 3D tissue in vitro. We expect to see a growing use of our kidney tissues in the coming years to model chronic kidney disease, and maybe even to help identify new therapeutic targets and biomarkers.”
She couldn’t disclose specific compounds currently being tested with the company’s pharma partners, but Nguyen says several compounds have been tested in proof-of-concept studies. In one of those studies, the Organovo team demonstrated induction of toxicity following treatment with the nephrotoxin cisplatin. Results showed a loss of tissue viability and epithelial cell function in a dose-dependent fashion. This effect was blocked by cimetidine, a compound that prevents cisplatin uptake via the transporter OCT2.
“In addition, work in partnership with colleagues from La Jolla Pharmaceuticals was presented at the recent Society of Toxicology meeting, showing the ability of the kidney tissues to model gentamicin-induced toxicity,” she says.
“The kidney is a complex organ, and there are other regions beyond the proximal tubule that are sensitive to drug-induced toxicity. To try and develop a model system to look at other regions of the nephron, we have formed a collaboration with Prof. Melissa Little from of the Murdoch Childrens Research Institute. Little and her team have demonstrated the ability to grow 'mini-kidneys' from induced pluripotent stem cells. We have licensed this technology in the hopes of developing a robust in-vitro system for investigating toxicity and disease pathways across the nephron. With Little’s incredible knowledge and successes in kidney development combined with our bioprinting technology, the teams are working to develop an architecturally correct kidney for potential therapeutic applications,” Nguyen concludes.