The experimental drug that could cure Autism-linked fragile X

Nutlin-3 reverses the damage caused by fragile X in mice.

In a study in Science Translational Medicine, researchers at the University of Wisconsin-Madison showed that Nutlin-3 improved memory and learning capacities in fragile X mice. Fragile X is the most common genetic intellectual disability in the world, affecting one in 4,000 boys and one in 7,000 girls, with more than one-third of sufferers also diagnosed with autism. So far, the disability has no cure. We talked to the study’s lead author, Xinyu Zhao, to discover what the next steps in this research are.

ResearchGate: Could you explain the significance of the results of your study for people with the fragile X disability? How did you come to these results?

Xinyu Zhao: We identified a new potential drug target for treating fragile X syndrome, which we hope will lead to further research in this area and, in the long run, a treatment of the disability. By using a combination of a bioinformatics analysis and a literature search, we found several genes that might be dysregulated in fragile X neural stem cells, including one that stood out to us – MDM2.

We then performed molecular and cell biology analysis to validate the significance of our finding. In the process, we discovered that cancer biologists who were also studying the MDM2 gene had already developed drug-like molecules in clinical trials that were designed to treat retinoblastoma, a kind of eye cancer. We decided to use one of these molecules, called Nutlin-3, to treat fragile X neural stem cells and mice with fragile X. Our results showed that Nutlin-3 can effectively reverse several defects that we observed in fragile X cells and mice, such as their memory capacity. The dose we used was only 10 percent of the dose that is being proposed for the treatment of retinoblastoma, and so far the drug hasn’t caused harmful side effects. We are still a long way from declaring a cure for fragile X, but these results are promising.

RG: What is fragile X and what does the disability have in common with Autism?

Zhao: Fragile X syndrome is a neurodevelopmental disorder that has a devastating effect on intellectual abilities, including memory deficits and learning difficulties. The syndrome is mostly the result of a single gene mutation, and about 40 percent of fragile X patients are also diagnosed with autism – in fact, the fragile X gene mutation is the largest single gene contributor to autism. Therefore, studying fragile X syndrome can serve as a gateway for understanding the biological mechanisms that cause autism.

RG: Can you explain why the condition is more prevalent in boys than girls?

Zhao: The fragile X gene is located on the X chromosome. As girls have two X chromosome, if one of the chromosomes has mutations, the girls may not get the disability, or the symptoms are likely to be much milder. As boys only have one X chromosome, if this chromosome is mutated they will have fragile X syndrome.

RG: What kind of treatment is currently available for sufferers of fragile X?

Zhao: Currently, there is no FDA approved treatment for fragile X syndrome. However, there are some medications for controlling certain symptoms, such as seizures.

RG: What are the next steps in your research?

Zhao: Our study treated adult mice, so I would like to know whether we can use this treatment at a younger age. I also hope to know how long a single period of treatment can last and how frequently we need to administer the treatment.

Image courtesy of Gregoniemeyer.