PROJECT 3: Targeting the D4Z4 sequence to enhance repeat repression Abstract FSHD is caused by mutations that decrease the efficiency of D4Z4 repeat-mediated epigenetic repression and result in the low-level variegated mis-expression of DUX4 in skeletal muscle. The broad and long-term goal of this project is to identify components and modulators of the pathways that epigenetically silence D4Z4 repeats that can be exploited to develop a therapy for FSHD, and potentially other human diseases. The major hypothesis of this project is that enhancing the efficiency of repeat-mediated epigenetic repression will suppress DUX4 expression in FSHD muscle and decrease, or reverse, the progression of disease. The specific goal of the project is to identify compounds, their mechanisms of action, and their pre-clinical efficacy in suppressing DUX4 expression in skeletal muscle. This will be accomplished by:
Aim 1, Identify and characterize drug-like compounds that enhance the epigenetic repression of D4Z4 and suppress DUX4 expression;
Aim 2, Determine the pathways and sequences necessary for D4Z4 epigenetic repression;
and Aim 3, perform preclinical development of oligonucleotides to enhance repression of D4Z4 and DUX4 expression. Together these aims will identify compounds, their mechanisms of action, and their pre-clinical efficacy in suppressing DUX4 expression in skeletal muscle. The significance of these studies is that they will identify compounds, their mechanisms of action, and their pre-clinical efficacy in suppressing DUX4 expression in skeletal muscle. The health relatedness is that these studies will provide the basis for future human clinical studies in FSHD.
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