New Strategy for Treating
Fragile X Syndrome
by Targeting Expression of
FMRP Using TBEV5'-UTR
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This year, our aim is to find a possible therapy for the fragile X syndrome, an intellectual disorder occurs mainly in young children. People suffering from the fragile X syndrome are both intellectually and emotionally disabled. According to some former researches, the disorder is mainly caused by the transcriptional silence of the FMR1 gene, due to added CGG repeats in the 5’-UTR of the gene. Normally, there are 5-45 repeats of CGG, but some may accumulate more than 200 repeats, which shuts down the transcription of FMR1 and causes reduction of FMR1 protein (FMRP). Due to this change in the gene, the transcripts normally regulated by FMRP are getting out of control, leading to disorder in the cell and finally to chaos in the brain.
In the process of finding the possible treatment, we decided to increase the content of FMRP, which seems to be easier compared with fixing gene. However, it is hard to add protein into neurons directly, so we try another method. For several years our team focus on targeted drugs, so this time we will continue working on this method.
It is known that the neuron has different body parts, the perikaryon, the dendrite and the axon. Each part of the cell has separate functions and varies in the kinds and amounts of certain proteins. Also, it is reported that the FMR-1 cannot work in the perikaryon, it needs to be transported to the dendrites of the neuron where the mRNA starts the construction of FMRP. This occurs to us that if we could deliver normal FMR1 genes into dendrites, the FMRP would be translated and function. But how can we make a target on the dendrites?
Luckily we found a recent study showing that a virus called TBEV is able to transport its own gene to the dendrites within the special structure of its 5’-UTR. We also found some previous studies have shown that the neuron has developed its own system by adding 3’-UTR to the mRNAs to transport them to the dendrites. Hence, what we are trying to do here is to create a special vector containing FMR1 gene attached to the sequence of certain untranslated regions, and this would be our special medicine. The main experiment in this stage is to test whether this combination of certain genes and 5’/3’-UTR works and which combination is most efficient in the transportation. We are expecting that TBEV wins the game. On our way of testing the transportation efficiency, we will passingly see if there are any tendency in the distribution of the mRNA like they favor some dendrites while dislike other ones. And models will be built to describe the distribution quantitatively at the time.
As long as the transportation and expression succeed, we will be able to add extra FMRP into the target cell to see if there are indeed some difference in supporting of transcript regulation in the dendrites. When they are all proved to work as we imagine, we will be so close to our initial goal, finding a possible way to cure the Fragile X Syndrome.