Nutlin-3 against brittle X chromosome syndrome

In experiments on mice, researchers at the University of Wisconsin-Madison, working under the guidance of Professor Xinyu Zhao, with the help of an antitumor drug, managed to eliminate the manifestations of mental retardation characteristic of a hereditary disease known as brittle X chromosome syndrome.

The syndrome of the brittle X chromosome occurs with a frequency of 1 case per 4,000 newborn boys and 7,000 newborn girls. It is caused by a mutation of the FMRP gene and is one of the most common hereditary causes of mental retardation. In 2011, Professor Zhao and colleagues demonstrated that deletion of the FMRP–encoding gene in the cells of the hippocampus, the region of the brain responsible for memory, causes mental retardation in mice similar to the abnormalities observed in patients with brittle X chromosome syndrome. This deletion had a particularly pronounced effect on nerve stem cells and new neurons forming in the hippocampus.

The image obtained using a confocal microscope shows nerve stem cells (green) of the mouse hippocampus, actively proliferating due to the expression of FMRP (red)– a protein necessary for cell growth and differentiation.

Researchers were interested in the fact that reactivation of FMRP production in new neurons made it possible to restore the possibility of forming new memories. However, the mechanism by which the absence of FMRP blocks the formation of neurons, as well as the possibility of practical application of the identified effect, remained unclear.

In their latest work, the authors described previously unknown stages of a complex chain reaction triggered by the loss of FMRP and leading to the fact that mice stop remembering what they saw and smelled recently. This allowed them to identify the experimental antitumor drug Nutlin-3 (Nutlin-3), blocking the last stages of this reaction.

As part of an experiment to test the animals' ability to memorize, they were placed in a closed enclosure in which they could freely move around two objects unknown to them. Curious by nature, the mice studied and sniffed each of the objects. After 10 minutes, the animals were removed from the enclosure, one of the objects was replaced with a new one, and after 24 hours they were placed back in the enclosure. Normal animals spent significantly more time studying an unknown object, whereas mice with a deletion of the FMRP gene did not remember the old object and studied it anew.

To test the ability of nutlin-3 to block the memory-disrupting reaction, the researchers added it to the feed of mice with a deletion of the FMRP gene for two weeks. The testing carried out 4 weeks later showed that the therapy completely restored the ability of mice with the simulated syndrome of the brittle X chromosome to memorize, while their behavior did not differ from the behavior of normal animals.

The authors note that the work with animals and the processing of experiments filmed on video were carried out by different people. At the same time, the researcher who analyzed the time intervals spent by mice on studying objects had no information about which animals he was dealing with, which is an additional confirmation of the reliability of the results.

Nutlin-3 is currently undergoing a phase I clinical trial as a treatment for retinoblastoma, a malignant tumor of the eye. This can speed up the process of obtaining permission to conduct clinical trials of its use in the treatment of brittle X-chromosome syndrome.

The dosage of the drug used in the experiments was only 10% of the dose proposed for use in retinoblastoma chemotherapy. At the same time, no side effects were observed in the animals. The authors also note that more than 30% of patients with brittle X chromosome syndrome are diagnosed with autism, so the data obtained can shed light on the mechanisms of development of this disease.

However, they emphasize that it is still very early to declare victory over the syndrome of the brittle X chromosome, as there is still a lot of work to be done and answers to many questions to be found.

The article by Yue Li et al. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome is published in the journal Science Translational Medicine.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Wisconsin—Madison: Experimental drug cancels effect from key intellectual disability gene in mice. 

16.05.2016