Can organoids guide clinical decisions? Current successes and potential pitfalls.

The organoid culture technique was first reported by the Clevers lab in 2009. They demonstrated the long-term culture of primary murine small intestinal tissue due to the maintenance of stem cells ex vivo. Since then, these techniques have been successfully transferred across different tissues from different species, often with minimal protocol modification required.

Publications suggest various applications for organoids such as the study of normal development and diseased tissues, cellular and gene therapy, drug screening and personalized medicine. The use of organoids has now begun in the clinic, which was reviewed in a recent Nature Medicine paper within the disease areas of cystic fibrosis and oncology.

The University Medical Centre (UMC) in the Netherlands have been utilizing patient-derived rectal organoids to direct treatment of patients with cystic fibrosis, an inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Rectal organoids can be induced to swell upon activation of CFTR, and UMC clinicians utilized this function as a readout to determine whether patients with mutations for which drugs are not currently approved, would respond to said treatment. Nearly 40 patients have now been treated based on results obtained from assays utilizing patient-derived rectal organoids in this manner.

Advances in the clinical use of organoids in oncology have highlighted some potential obstacles. The time from biopsy to obtaining organoid assay results can be up to 6 months, which limits the benefits to those without advanced disease. The factors involved include the differing growth rates between cancer types and patients, and the amount of tumour tissue obtained from biopsies.

However, there are still programs comparing the clinical response of patients to that of their tumour organoids, with similar drug responses already observed. In addition, work performed on patient-derived prostate tumour organoids has led to the initiation of a Phase 1 clinical trial testing inhibitors of enhancer of zeste homolog 2 (EZH2), a protein shown to promote proliferation.

Other issues to address include regulation of use within the clinic and co-operation of insurance companies. Earlier this year the Hubrecht Organoid Technology, founded on the work by the Clevers group, and three Dutch insurance companies announced a validation trial for the use of organoids as a decision tool. It is hoped this will allow the payment of novel treatments whilst avoiding treatments that potentially do not work.

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Epistem's Organoid Models

Epistem have presented developmental work within the organoid model in the areas of epithelial regeneration and GI toxicity at various conferences.

Potential readouts in this model could be proliferation, differentiation, apoptosis, cytotoxicity screening and protein and gene expression.

Chakradhar, S. (2011). “Put to the test: Organoid‑based testing becomes a clinical tool.” PNAS.

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