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FAST Introduces New Research Program for Development of a potential miRNA Therapeutic

FAST, the Foundation for Angelman Syndrome Therapeutics, is pleased to unveil a research plan for the development of a microRNA (miRNA) approach as a potential therapeutic for the treatment of Angelman syndrome (AS). FAST is actively funding numerous research initiatives in gene and protein replacement therapies, as well as other disease-modifying approaches. In collaboration with the Gene Therapy Program at the University of Pennsylvania, the latest research plan will build on the milestones already achieved with CRISPR-Cas9/sgRNA interference of the UBE3A-antisense transcript (UBE3A-AS) to develop a novel strategy to suppress UBE3A-AS extension utilizing miRNAs. 

This potential therapeutic advancement relies on an miRNA-mediated targeting of the UBE3A-AS to increase UBE3A protein levels in Angelman syndrome neurons. Inhibiting the expression of the UBE3A-AS can result in the expression of the UBE3A gene on the paternal allele, which is normally silenced in neurons of all individuals. This phenomenon is known as imprinting. Antisense oligonucleotides (ASOs), clustered regularly interspaced short palindromic repeats-guide-RNA (CRISPR-gRNA), short-hairpin RNAs (shRNA), and other technologies, such as this platform of miRNA, can exploit this imprinting phenomenon and “unsilence” the paternal UBE3A gene, resulting in UBE3A protein expression in neurons. Antisense oligonucleotides (ASOs), currently being investigated clinically in humans with AS, aim to prevent this normal silencing of the paternal UBE3A gene, yet it does not achieve this goal permanently, requiring repeated treatments. Because miRNAs are subject to cellular processing and regulation, this can potentially help to bypass issues related to overexpression of genetic material with UBE3A gene replacement, while also avoiding the need for repeated redosing. 

Previous studies have shown that interfering with mouse UBE3A-AS results in paternal UBE3A expression, creating a therapeutic benefit in the Angelman syndrome mouse model, rescuing some of the known symptoms of AS that the mouse exhibits. Based on the current research, the Department of Medicine for the University of Pennsylvania hypothesizes that the expression of miRNAs that selectively target the UBE3A-AS can deliver a lasting therapeutic benefit for individuals with Angelman syndrome after a single-dose administration. Building on current research, completion of the proposed experiments establishes a realistic aim for identifying a clinical candidate for treating Angelman syndrome within 1 year.

FAST is excited to collaborate with gene therapy pioneer James Wilson, MD, Ph.D., and his team at the University of Pennsylvania for this latest research development. “Building on the success of the ASO therapies for Angelman, we hope to restore functional paternal UBE3A protein with a single administration of gene therapy. An optimized microRNA should achieve long term clinical effects by stably knocking down the UBE3A antisense RNA.” states Dr. Wilson.

All conditions of Angelman syndrome involve a disruption to the UBE3A gene on the maternal 15th chromosome. FAST is aggressively pursuing numerous therapeutic strategies to ensure that a meaningful therapeutic will be available for all genotypes and all ages. This program is another step closer to ensuring that we, at FAST, leave no stone unturned.  

To learn more about FAST, please visit Consider contributing to FAST by making a financial gift, spreading the word with friends and family members, and fundraising to help FAST cross the finish line.