Evaluating mice bearing Ube3a mutations with a set of five behavioral tests may be a useful tool for preclinical therapy testing to identify treatments for Angelman syndrome, a study suggests.
The study, “A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants,” was published in the journal Molecular Autism.
Mouse models are important tools for detailed biological processes linked to disease, as well as preclinical assessment of new therapies. However, for the retrieved information to have medical validity, the models must effectively mimic human disease to the greatest extent possible. Also, the measures used to assess the animals and their clinical manifestations must accurately identify markers of the disease.
Researchers at Erasmus Medical Center in the Netherlands proposed a set of five standardized tests to evaluate mice engineered to have Ube3a gene mutations, the genetic cause of Angelman syndrome.
The first test measures the time animals are able to maintain their balance on top of an accelerating cylinder, allowing them to measure mice motor function.
“Individuals with Angelman syndrome show clear motor impairments, and impaired performance on the accelerating rotarod is the most frequently described phenotype in Ube3a mice,” researchers wrote.
In the second test, animals are placed in an open field and allowed to walk freely. Researchers are then able to evaluate their anxiety levels and locomotor skills.
The physical capacity of mice is tested using a forced swim test. The animals are placed in a cylindrical tank of water for two minutes. Researchers then record the time during which the mice actively swim or just float.
Nest-building and marble-burying tests are used to see whether animals retain common behaviors of their species. In these tests, nest-building materials or marbles are placed inside mice’s cages and researchers record whether the animals either build a nest or bury the marbles.
The team applied these tests to 111 Ube3a mutated mice and 120 healthy controls. Ill mice consistently showed impaired response in all five tests. They had reduced balance and locomotor skills, spent more time floating, used less material to build their nests, and buried fewer marbles than control mice.
To further confirm these results, researchers repeated the experiments with two different mouse models bearing Ube3a mutations. The results were consistent to those reported in the first model.
“Taken together, these data suggest that the identified set of behavioral [manifestations] in this test battery is present in three independently derived Ube3a-mutant lines,” researchers wrote.
Although these tests cover several of the main manifestations of the human disease presentation,“a paradigm that assesses cognitive function” is lacking — “an important clinical feature of Angelman disease,” researchers noted.
In humans, Ube3a mutations are linked to profound cognitive impairments. However, in these mouse models, learning deficits “are rather mild,”researchers said.
To explore the preclinical potential of this battery of tests, the team treated Ube3a mutated mice with minocycline and levodopa and assessed the impact of the therapies. These two therapies have been tested in clinical trials in patients (NCT01531582, NCT02056665, NCT01281475), but have failed to demonstrate efficiency despite positive preclinical data.
Similar to what happened in the clinical trials, the two investigational compounds failed to promote significant improvements in all five test results, reinforcing that this behavioral evaluation approach can effectively screen for therapies that are more likely to be successful in clinical trials.
Because the behavioral impairments “are observed in several independently derived Ube3a lines,” researchers believe that this test battery “can also be employed to investigate the effect of specific Ube3a mutations.”
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