Dave’s Research Corner
Each quarter, we like to share a research article about APS Type 1 to help keep us all up to date. This time, we share a recent article entitled “AIRE deficiency, from preclinical models to human APECED disease.”
Animal models are very important because they help us understand the intricacies of rare diseases. Researchers have developed six APS Type 1 mouse models, and in 2018, the Guillonneau lab developed rat model. The team of researchers that created this most recent model:
- trace the history of the development of animal models to study APS Type 1,
- explain why these models are important, and
- forecast the direction of the next advances in APS Type 1 research that may lead to a cure.
The contributions of Dr. Mark Anderson, a member of our Medical Advisory Committee, are highlighted numerous times in this interesting, highly-informative and well-written article.
Animal models have been essential to study and get a better understanding of the APECED disease, from its basic science to the development and assessment of novel therapies. The first knockout mouse was created in 1989. However, the first AIRE knockout mouse wasn’t created until 2002. In 2018, the Guillonneau lab created the first AIRE knockout rat, an in vivo model, that “recapitulate(s) several pathological hallmarks of the human disease” (i.e., showed signs of APS Type 1 similar to their human counterparts, including alopecia, vitiligo, and nail dystrophy.
In this article, several members from the Guillonneau lab trace the history of the development of the in vivo models (mice and rat) of APS Type 1 and discuss their limitations and advantages. They then go on to discuss ex vivo models of the disease specifically organoid and stem cell-derived models that will be the next step in finding a cure for APS Type 1.
AIRE DEFICIENCY, FROM PRECLINICAL MODELS TO HUMAN APECED DISEASE
Marine Besnard, Francine Padonou, Nathan Provin, Matthieu Giraud, Carole Guillonneau
Disease Models & Mechanisms
“To date, 145 AIRE mutations, including numerous mutant alleles, have been associated with APECED, from single-nucleotide mutations to large deletions across the gene’s entire coding sequence.”
“To study the role of AIRE in the establishment and/or maintenance of immunological tolerance, several rodent models of APECED disease were generated by inactivating Aire in mice and rats. Here, we summarize all existing preclinical models of APECED, highlighting their strengths and limitations in relation to human APECED pathology.”
“A key goal of APECED research is to derive iPSCs (Induced pluripotent stem cells) from the somatic cells of patients and then use gene editing to correct their endogenous AIRE gene mutations. The gene-edited iPSCs could then be differentiated into functional mTECs (Medullary thymic epithelial cells) that express the restored AIRE protein and all the AIRE-dependent and -independent TRAs. This approach could result in promising clinical applications, notably cell therapies, where corrected syngeneic mTECs are transplanted to restore the functionality of thymic tissue.”
“Differentiation of iPSCs into functional thymic tissue will enable functional T cells differentiation ex vivo, thereby providing a unique opportunity to restore a dysfunctional immune system through personalized cell therapy treatments.”