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The genetic changes that occur at the D4Z4 repeat region are widely thought to be a causative factor in the initiation and progression of FSHD. These unique changes in the DNA sequence lead to the production of the highly toxic Dux4 protein in muscles, which ultimately lead to the progressive loss in their function. Thanks to the hard work of the FSHD scientific community, we now understand how changes in the DNA sequence at the D4Z4 locus leads to the production of Dux4. A key feature of these alterations is that Dux4 gene attains the ability to produce a messenger RNA through a process called cleavage and polyadenylation. Preventing the cleavage and polyadenylation using molecular antagonists could inhibit this process thereby reducing production of Dux4 and potentially alleviating FSHD symptoms or even preventing them altogether.
My laboratory interests are focused solely on the cleavage and polyadenylation process and we have developed significant preliminary results on Dux4. Using a novel fluorescence-based reporter system that we have developed, we identified a key element within the DNA sequence critical to make Dux4 messenger RNA that is a prime candidate for molecular antagonism. Here, we will utilize our reporter technology to test antisense oligonucleotides (AONs) to determine their effectiveness in antagonizing Dux4 cleavage and polyadenylation. Candidate AONs will then be applied to FSHD patient cells to measure how well they are able to reduce Dux4 expression. Finally, we will use Deep Sequencing technology to assess side effects of AON treatment in patient cells. The use of AON is becoming more mainstream in the treatment of human disease and AONs are currently in clinical trials for the treatment of several human pathological states including Spinal Muscular Atrophy. Our approach is highly directed for Dux4 cleavage and polyadenylation and we have all of the tools necessary to quickly assess AON effectiveness and off-target effects in patient cells. Successful completion of this project could lead to the rapid development of a novel therapeutic for the treatment of FSHD.