Rare diseases represent a large disease segment even though each disease impacts a small number of people – over 7000 rare diseases have been identified and about 300 million people have a rare disease1. Most rare diseases (80%) have a genetic driver but only about 5% of rare diseases have an approved therapy1. Therefore, the unmet clinical need for rare diseases is very high and this is compounded by the fact that most rare disease patients are children who have a short time window for treatment. In this scenario, the typical drug development timeline of a decade and involves the development of preclinical in vitro and in vivo models. While preclinical animal models of rare disease can be engineered using gene editing technologies, they often do not recapitulate the disease hallmarks and have limited utility to screen therapies.
A viable alternative is the development of in vitro organoid models that use patient tissue as the starting material. These models are called patient-derived organoids or PDOs and are referred to as “disease in the dish”. Typically, PDOs are grown from induced pluripotent stem cells or iPSCs that are reprogrammed from patient tissues, so they contain all the disease genetic drivers. PDOs are considered to be better models compared to organoids generated from healthy tissues that are genetically engineered using CRISPR or other gene editing technologies to include disease specific mutations. Additionally, PDOs allow researchers to study complex idiopathic diseases and facilitate the understanding of genetic and disease development differences in patient populations, which can be an advantage and a challenge. There can be multiple underlying mechanisms for a given disease, and PDOs allow granular analysis of the signaling and disease development changes in different segments of a specific patient populations. This can result in highly variable PDO populations that poses analytical and statistical challenges. Another important application of PDOs is to support the understanding of drug-gene interactions at the individual patient level. This gives information on whether a patient can metabolize and distribute a drug sufficiently or whether there are adverse interactions between two drugs in a specific patient2. PDOs can be used to test the efficiency of disease mutation correction using gene editing technology.
One of the earliest reports of PDO applications was from the University of Utrecht who developed PDOs from rectal biopsies of cystic fibrosis patients that were shown to be a good platform screen novel therapies3. Interestingly, a more recent study showed that organoids derived from induced pluripotent stem cells (iPSCs) of a CF patient with the F508del mutation could be corrected by TALENS gene-editingwhere TALENS-mediated homologous recombination was used to remove the three-nucleotide defect in the CFTR gene—essentially correcting the disease-causing genetic defect4. Gastrointestinal rare diseases are another area of active PDO development as adult stem cell-derived PDOs are a well-established method. A recent publication reported the development of PDOs from patients with microvillus inclusion disease (MVID), a rare congenital enteropathy that has a high mortality rate in children and currently has no treatment5. Interestingly, the researchers were successful in developing the PDOs from 2 pediatric patients that successfully recapitulated the disease phenotype. The PDOs were shown to be a robust platform to test antidiarrheal medication as well as g-secretase inhibitors as potential therapies and were also used to perform transcriptomic analysis to identify new more specific therapeutic targets5. Researchers are actively developing new and improved methods of organoid development for multiple tissue types so it is likely that organoids developed from patient tissues will become a standard platform to study disease biology and evaluate novel therapies for rare diseases.
References:
1https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(24)00056-1/fulltext
2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241074/
3https://pubmed.ncbi.nlm.nih.gov/23727931/
