Organoids provide an opportunity to create cellular models of human disease, which can be studied in the laboratory to better understand the causes of disease and identify possible treatments. The power of organoids in this regard was first shown for a genetic form of microcephaly, where patient cells were used to make cerebral organoids, which were smaller and showed abnormalities in early generation of neurons. In another example, the genome editing system called CRISPR was applied to human pluripotent stem cells to introduce targeted mutations in genes relevant to two different kidney diseases, polycystic kidney disease and focal segmental glomerulosclerosis. These CRISPR-modified pluripotent stem cells were subsequently grown into human kidney organoids, which exhibited disease-specific phenotypes. Kidney organoids from stem cells with polycystic kidney disease mutations formed large, translucent cyst structures from kidney tubules. When cultured in the absence of adherent cues (in suspension), these cysts reached sizes of 1 cm in diameter over several months. Kidney organoids with mutations in a gene linked to focal segmental glomerulosclerosis developed junctional defects between podocytes, the filtering cells affected in that disease. Importantly, these disease phenotypes were absent in control organoids of identical genetic background, but lacking the CRISPR mutations. Comparison of these organoid phenotypes to diseased tissues from mice and humans suggested similarities to defects in early development.
As first developed by Takahashi and Yamanaka in 2007, induced pluripotent stem cells (iPSC) can also be reprogrammed from patient skin fibroblasts. These stem cells carry the exact genetic background of the patient including any genetic mutations which might contribute to the development of human disease. Differentiation of these cells into kidney organoids has been performed from patients with Lowe Syndrome due to ORCL1 mutations. This report compared kidney organoids differentiated from patient iPSC to unrelated control iPSC and demonstrated an inability of patient kidney cells to mobilise transcription factor SIX2 from the golgi complex. Because SIX2 is a well characterised marker of nephron progenitor cells in the cap mesenchyme, the authors concluded that renal disease frequently seen in Lowe Syndrome (global failure of proximal tubule reabsorption or renal Fanconi syndrome) could be related to alteration in nephron patterning arising from nephron progenitor cells lacking this important SIX2 gene expression.
Other studies have used CRISPR gene editing to correct the patients mutation in the patient iPSC cells to create an isogenic control, which can be performed simultaneously with iPSC reprogramming. Comparison of a patient iPSC derived organoid against an isogenic control is the current gold standard in the field as it permits isolation of the mutation of interest as the only variable within the experimental model. In one such report, kidney organoids derived from iPSC of a patient with Mainzer-Saldino Syndrome due to compound heterozygous mutations in IFT140 were compared to an isogenic control organoid in which an IFT140' variant giving rise to a non-viable mRNA transcript was corrected by CRISPR. Patient kidney organoids demonstrated abnormal ciliary morphology consistent with existing animal models which was rescued to wild type morphology in the gene corrected organoids. Comparative transcriptional profiling of epithelial cells purified from patient and control organoids highlighted pathways involved in cell polarity, cell-cell junctions and dynein motor assembly, some of which had been implicated for other genotypes within the phenotypic family of renal ciliopathies.  Another report utilising an isogenic control demonstrated abnormal nephrin localisation in the glomeruli of kidney organoids generated from a patient with congenital nephrotic syndrome.
Things such as epithelial metabolism can also be modelled.