Genetically modified mice open the door to personalized medicine in rare diseases

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

Patients with mutations in this protein have Allan-Herndon-Dudley syndromea rare disease that is manifested by serious neurological changes and in which every patient can have a non-MCT8 mutation.

In this work, published in Neurobiology of disease, the first avatar model of the disease is described, i.e. the first animal with the same genetic change of several patients.

This is the basis for studying the possible ‘genetic repair’ of this mutation in an animal model and assessing whether it is possible to avoid or reverse the serious neurological changes that exist in these patients

Carmen Grijota

“The development of avatar models that faithfully reproduce the changes of patients with the same mutation is the first step towards targeted therapy. More precisely, it is the basis for the possibility of studying the possible ‘genetic repair’ of this mutation in an animal model and assessing whether it is possible to avoid or reverse the serious neurological changes that exist in these patients”, justifies the importance of the study Carmen Grijotaresearcher at the Department of Cell Biology at UCM and at IIBM.

The same neurological and motor changes in avatars and humans

For this study, mice carrying “P321L” mutation. Tests were conducted to examine the behavior, anxiety level and motor coordination ability of the mice. The brains of these animals were then extracted and specific stains were performed to visualize and study the different types of neurons.

“Finally, thoroughly computer analysis to understand how the mutation could affect the structure of the MCT8 transporter, and thus its thyroid hormone transport function,” he adds. Victor ValcarcelIIBM researcher and co-author of this paper.

An in-depth computational analysis was performed to understand how the mutation might affect the structure of the MCT8 transporter and thus its thyroid hormone transport function.

Victor Valcarcel

Among the changes presented by the mice, were found cerebral hypothyroidism (lack of thyroid hormone in the brain), hyperthyroidism (excess of thyroid hormone in other tissues), changes in the distribution of neurons in the cerebral cortex and reduction of GABAergic neurons. Furthermore, impaired motor coordination and anxious behavior were observed in mutant mice. All these findings reflect the characteristic changes of patients with this disease.

In the next steps in this line of research, scientists progress, will be administration of medicine which mimic the activity of thyroid hormone, but do not need MCT8 to enter cells because they use different transporters. “The idea is to see if these drugs can get to the brain of a mutant mouse and improve all these changes,” he says. Marina GuillénIIBM researcher.

The idea is to see if these drugs can reach the brain of the mutant mouse and improve all these changes

Marina Guillén

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

Reference:

Víctor Valcárcel-Hernández et al. “A CRISPR/Cas9 engineered avatar mouse model deficient in monocarboxylate transporter 8 exhibits distinct neurological changes”. Neurobiology of disease

Rights: Creative Commons.

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