Genetically modified mice open the door to personalized medicine in a rare disease

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An international research team led by Dr. Ana Guadaño at the Alberto Sols Biomedical Research Institute (IIBM, mixed CSIC-UAM center) in which the Complutense University of Madrid (UCM) participates has introduced in mice –using genetic editing techniques CRISPR–, a mutation of the MCT8 protein, responsible for the transport of thyroid hormones into the cell.

Patients with mutations in this protein suffer from Allan-Herndon-Dudley syndrome, a rare disease that manifests with severe neurological disorders and in which each patient may have a different MCT8 mutation.

In this work, published inNeurobiology of Disease‘, the first avatar model of the disease is described, that is, the first animal with the same genetic alteration of several patients.

“The development of avatar models that faithfully reproduce the alterations of patients with the same mutation is the first step towards targeted therapy. Specifically, it is the basis for being able to study the possible ‘genetic repair’ of that mutation in an animal model and to assess whether it is possible to avoid or reverse the serious neurological alterations that exist in these patients”, justifies the importance of the study by Carmen Grijota, a researcher at the Department of Cell Biology at the UCM and at the IIBM.

Same neurological and motor alterations in avatars and humans

Mice carrying the “P321L” mutation were used for this study. Tests were carried out to study the behavior, anxiety levels and motor coordination capacity of the mice. Next, the brain of these animals was extracted and specific stains were performed to visualize and study different neuronal types.

“Finally, an in-depth computer analysis has been carried out to understand how the mutation may be affecting the structure of the MCT8 transporter and therefore its thyroid hormone transport function”, adds Víctor Valcárcel, a researcher at the IIBM and co-author of this work.

Among the alterations that the mice presented, cerebral hypothyroidism (lack of thyroid hormones in the brain), hyperthyroidism (excess of thyroid hormones in the rest of the tissues), alterations in the distribution of neurons in the cerebral cortex and a decrease in GABAergic neurons. Furthermore, impaired motor coordination and anxious behavior were noted in the mutant mice. All these findings reflect the characteristic alterations of patients with this disease.

In the next steps in this line of research, the scientists advance, would be the administration of drugs that mimic the activity of thyroid hormones, but that do not need MCT8 to pass into the cells because they use different transporters. “The idea is to check whether these drugs are capable of reaching the mutant mouse brain and improving all these alterations,” says Marina Guillén, a researcher at the IIBM.

In addition to these two institutions, the Institute of Functional Genomics of Lyon (France) and the University of Bristol (United Kingdom) participate in the work.


Víctor Valcárcel-Hernández et al. ‘A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations’. Neurobiology of Disease

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