Study employs gene reactivation to treat Fragile X syndrome

Fragile X syndrome, or FXS—a principal genetic cause of autism—impacts around one in 6,000 females and one in 4,000 males. The symptoms include intellectual disability, increased anxiety, social communication deficits, repetitive behaviors, and abnormal sensory processing.

Iryna Ethell, fourth from left, is seen here with some coauthors of the research paper. First author, Maham Rais, is third from left. Image Credit: University of California–Riverside/Ethell lab.

Individuals thriving with FXS normally lack the fragile X mental retardation 1 gene, or Fmr1, in their brain cells. Even if the cells retain this gene, it is silent and does not produce a protein named FMRP.

Scientists from the University of California, Riverside ameliorated the FXS symptoms by inserting Fmr1 into the brains of very young transgenic mice which were genetically engineered to lack this gene. The scientists then evaluated the brain activity for signs of hyperactivity and anxiety in response to stimuli like sounds and stresses.

They observed that upon reactivation of the Fmr1 gene in the mice no symptoms of FXS were noticed. The study was published in the Neurobiology of Disease journal.

Our work shows beneficial effects of reactivating the Fmr1 gene, which would be very welcome news for young children living with FXS.”

Iryna M. Ethell, Professor, Biomedical Sciences, School of Medicine, University of California–Riverside

Professor Ethell headed the study.

In the current research, Ethell’s lab, in association with Khaleel A. Razak, a professor of psychology, chose very young mice—less than three weeks old—as the brains are more pliable early in life; in humans, the equivalent is around the first 3–5 years.

Ethell adds, “For humans, the first 3–5 years are critical in brain development. It’s important, therefore, that this early period be targeted in FXS.”

The mouse brain—similar to the human brain—contains inhibitory and excitatory neurons. In contrast to excitatory neurons that direct to a forward propagation of information, inhibitory neurons function as a brake by inhibiting unwanted activity and tuning brain activity to certain signals.

Ethell and two other co-workers recently published a review article in Nature Neuroscience indicating that that the dysfunction of inhibitory neurons is a usual pathology in genetic diseases that are associated with autistic spectrum disorders or ASD.

In the current study, we targeted excitatory neurons in the second and third postnatal weeks of the mice to insert the Fmr1 gene. Our study shows this period is not too late for manipulating the brain. We targeted these particular neurons because they establish control over inhibitory neurons that are malfunctioning in FXS. At this time, we do not know if our method would be effective in adults. That research would be a next step in this line of work.”

Iryna M. Ethell, Professor, Biomedical Sciences, School of Medicine, University of California–Riverside

The approach through which Ethell and her associates inserted the Fmr1 gene into mouse brains vary from how the gene will be introduced into a human brain. However, Ethell states that the outcome will be the same. She also added that CRISPR, a robust tool genome editing will most likely be utilized to reactivate Fmr1 in the human brain.

FXS is most often diagnosed early in a person’s life. We cannot stress enough, therefore, that the early years are the perfect time to reactivate the Fmr1 gene. It offers hope that even if this gene is missing in a child, it can still be introduced, allowing the child to live a daily life free of FXS.

Iryna M. Ethell, Professor, Biomedical Sciences, School of Medicine, University of California–Riverside

Ethell further adds, “As gene reactivation to treat FXS receives increasing attention, our results suggest the benefits of Fmr1 re-expression during the early period of brain plasticity in mice, which roughly corresponds to the first three years of human life, when ASD symptoms first emerge in infancy.”

The scientists further intend to work on restoring function in the adult FXS brain.

“The main challenge is that the adult brain is not so plastic. Young brains can do just about anything. But as an adult, have you tried to learn a new language?” concluded Ethell.