A University of Calgary team attempting to reverse symptoms of fragile X syndrome (FXS) in mice was awarded a $100,000 grant by the FRAXA Research Foundation and the Fragile X Research Foundation of Canada.
Fragile X syndrome, the most common genetic cause of autism, is caused by lack of an RNA-binding protein called FMRP. This protein regulates the production of other proteins during brain development, which are key for normal communication between nerve cells. Loss of FMRP results in reduced ability of these cells to fine-tune their responses based on prior experience, a process known as plasticity.
Researchers are trying to find an effective and safe strategy to reintroduce FMRP into nerve cells. Their approach is to attach a tiny chain of amino acids — the building blocks of proteins — called TAT, to a fragment of the FMRP protein.
TAT is used as a sort of GPS, guiding the FMRP segment to the brain and improving its delivery into nerve cells. The use of a segment, rather than a normal-sized protein, is due to the large size of the full FMRP protein, which becomes an obstacle to its transport. Using an FMRP segment also may avoid dosage issues seen in previous studies of protein replacement.
The team is focused on a specific cellular pathway through which a type of nerve fibers, called mossy fibers, activate a certain type of nerve cells (granule cells) in the mouse’s cerebellum. They have found that FMRP increases granule cell excitability and that mice without FMRP completely lack this mossy fiber-mediated activation of granule cells. Infusion of an active fragment of FMRP into these cells restored their function.
In addition, injection of a TAT-FMRP construct into the bloodstream readily crossed the blood-brain barrier, which one of the main obstacles to overcome for any type of therapy targeting the brain, and successfully entered nerve cells.
Preliminary behavioral assessments indicated reduced hyperactivity of mice lacking FMRP within hours of injecting TAT-FMRP.
“These results are exciting in providing a glimpse into the potential to reintroduce FMRP as a potential therapeutic strategy to reduce abnormal behaviors in [FXS],” Raymond Turner, PhD, the team’s principal investigator, said in a press release.
According to Turner, the project will evaluate the precise cellular processes by which FMRP restores nerve cell communication and how to effectively promote behavioral benefits with TAT-FMRP.