Intestinal organoids helped patients with rare cystic fibrosis variants gain access to therapy; organoid-guided treatment did not shrink tumors in six patients with cancer
Intestinal organoids helped patients with rare cystic fibrosis variants gain access to therapy; organoid-guided treatment did not shrink tumors in six patients with cancer
On August 21, an essay on organoids compared two uses. In metastatic cancer, organoids currently help test research ideas. In cystic fibrosis, measuring CFTR channel function helps assess rare gene variants and responses to treatment.
An organoid is a tissue model grown from cells that retains some features of the original tissue, including layers, internal cavities, and connections between cells. This structure is useful when it converts cellular activity into a measurement that can inform a medical decision.
A tumor organoid shows how a patient’s cells respond to a drug. This type of test is well suited to chemotherapy because these drugs act inside dividing cells. In a pilot study, six patients with metastatic colorectal cancer received treatment selected according to the responses of their organoids; none of their tumors shrank. The essay’s author assigns tumor organoids a different role: selecting research programs. A bank of 256 tumor organoids illustrates this role. Researchers disabled genes and compared the cultures’ dependence on those genes for growth with their sensitivity to drugs.
In cystic fibrosis, variants in the CFTR gene can impair the CFTR protein channel, which conducts chloride across epithelial cells. It is difficult to recruit a separate clinical trial group for every rare variant. Researchers therefore need to measure the function of a specific variant and its response to a modulator drug that improves channel function.
For this purpose, researchers grow a patient’s intestinal organoid from a small rectal tissue sample. The result is a hollow, fluid-filled structure. A 2013 study described the FIS assay. Forskolin causes functional CFTR channels to open, chloride enters the internal cavity, water follows, and the organoid swells. Organoids from healthy participants swelled rapidly, whereas those from participants with cystic fibrosis swelled much less.
In a study of eight rare CFTR variants, researchers compared FIS results with responses to CFTR modulators. Six participants started treatment, and the authors recorded improved lung function and lower sweat chloride levels. In this case, the tissue structure makes channel function measurable and gives the physician additional information when selecting treatment for an individual patient.
The essay applies the same criterion to a model of the developing cortex exposed to Zika virus and to a culture derived from tonsil cells for studying the immune response. In the first case, organoids added evidence that the virus damages neural progenitor cells. In the second, the culture preserved the cellular interactions required for antibody production. The author uses these examples to ask what decision the model can inform: a choice of treatment, the next experiment, or a research program.