Development of Antisense oligonucleotide (ASO) therapies at ENDD is led by Dr. Benjamin Prosser, whose daughter has STXBP1 disorder. ASOs are short synthetic DNA-like molecules that bind target messenger RNA (mRNA) and alter the function of the RNA via several different molecular mechanisms, including disrupting secondary structure, inhibiting the formation of repressive RNA/protein complexes, and affecting mRNA splicing.
ENDD is working to develop several ASO approaches designed to increase expression of the functional protein to compensate for haploinsufficiency (loss of one functioning copy of either STXBP1 or SYNGAP). One such strategy is to use steric-blocking ASOs to prevent microRNA-based repression of STXBP1 or SYNGAP1 to increase protein expression to levels predicted to be therapeutic. Other examples are ASOs that affect mRNA processing through targeting alternative splicing, or by promoting translation initiation. Ultimately, we plan to develop multiple ASO strategies, as well as other gene-targeted modalities, which we test in human neuronal models and in humanized rodent models.