Kidneys are critical organs, playing a key role in homeostasis. They regulate a diverse range of functions – removing waste products, regulating water and electrolytes, and controlling blood pressure.
Many drugs are at least partly excreted and metabolised by the kidneys. As a result, toxic effects can be exerted within the kidney and can be further exacerbated where urine is more concentrated.
Human kidney samples are typically limited to post-mortem samples, organs unsuitable for transplantation and the additional tissue – presumed normal – adjacent to tumour tissue. Original samples are often suboptimal, which limits the use of primary kidney cells for investigating drugeffects on the kidney.
Pre-clinical drug discovery is currently reliant on 2D immortalised cell lines or primary cultures of rodent cells together with animal models. Cell models often contain a single cell type and don’t reflect the complex biology of the kidney, that is composed of many cell types. Animal models offer the complexity of an intact organ but lack human physiology.
These pre-clinical models may not be as predictive of the safety and efficacy in a human when progressing new drugs.
The challenge is to create 3D kidney models that are more predictive of potential drug toxicity and efficacy in the clinic.
Human iPSC-derived kidney organoids
Stem cells have the unique ability to develop into almost any cell type in the body. They represent an exciting area in medicine and can be utilised to understand disease processes, develop new targeted drugs, and for potential cellular therapies.
Induced Pluripotent Stem Cells (iPSC) are derived from skin or blood cells and have been reprogrammed back into an embryonic-like pluripotent state. This enables scientists to create an unlimited number of any type of human cell.
The team applied specific growth factors and inhibitors to human iPSCs to mimic the developmental processes which occur in the formation of the kidney. This resulted in the formation of 10 distinct kidney cell types which spontaneously self-organise into segmented nephron structures. These ‘mini kidney’ organoids comprise all the anticipated kidney features, including glomeruli, proximal tubules, loop of Henle and distal tubule as well as the collecting duct, endothelial network, and renal interstitium.
These multi-cellular 3D kidney organoids represent an infinite source of human kidney cell types and have the potential to transform both disease modelling and drug discovery approaches.
Medicines Discovery Catapult’s team are creating a variety of different kidney organoid models. Building internal capabilities and seeking drug discovery partnership opportunities with universities and SMEs.
Using iPSC it will be possible to create:
- Organoids that represent any organ
- Personalised organoids – providing an exact genetic match to a specific person
- Models of health (toxicity testing) and disease (efficacy testing)
The current 2D cell and animal models are inadequate in predicting normal physiological responses. Nephrotoxicity currently causes only 2% of compound attrition in pre-clinical testing. When these compounds progress to phase III clinical trials this translates to a 19% attrition rate in man. Many animal models of kidney disease are also not predictive of human response to drugs.
3D kidney organoid models, which may be more comparable to human tissue in both the cell types present and their structural arrangement, have the potential to improve predictability in pre-clinical testing. Reducing the need for less predictive 2D cell or animal models.
Further organoid model development is required to test their potential to address specific translational drug discovery challenges. These models are starting to be used for specific applications, and the data required to test their predictive ability in pre-clinical studies is now being generated.
In the long-term, these models could support regenerative medicine applications, such as cellular therapy, and could one day become sophisticated enough to replace the need to wait for a human organ transplant.