FAST’s Roadmap is focused on three elements supporting therapeutic approaches that have the potential to reverse the effects of the disorder in children, teens and adults.
FAST is funding research in gene or protein replacement therapy and paternal gene activation therapy.
Gene or protein replacement therapy delivers healthy copies of the UBE3A gene or protein to compensate for the missing or underperforming gene. Treatment is delivered via a viral capsid called Adeno-Associated Virus (AAV-GT) or through Hematopoietic Stem Cell therapy using a Lentivirus (HSC-GT).
Paternal gene activation therapy, in AS referred to as “stopping the stop”, works to activate the normally silent paternal gene to compensate for the underperforming or missing maternally inherited gene. These therapeutic platforms include antisense oligonucleotides (ASOs), CRISPR-CAS9, CRISPR-CAS13, shRNA, and others. Currently ASOs are being evaluated in human clinical trials for AS.
Downstream therapy includes drugs that treat the symptoms of Angelman syndrome like seizures, sleep, behaviors, etc. There are many drugs that are already approved by the FDA that might be useful for treating AS, but are not labelled for AS. Finding these drugs and showing that they can be repurposed can help to bring new treatments for AS.
Therapeutics being targeted often improve synaptic function and communication between neurons in the brain thus improving symptoms and therefore quality of life. Different strategies being pursued include: novel compounds or peptides, ketone supplements, anti-inflammatory or regenerative medicines, and GABA replacement therapies.
As FAST helps to prepare for clinical trials there are many important things that must be supported. Firstly, creating animal models and cell lines for each genotype, or type, of AS is important to ensure that we know how drugs can behave in different individuals. FAST has created a rat, pig and numerous mouse models of AS. Additionally, FAST supports the Global AS Registry and the AS Natural History studies that collect key data from those living with AS to understand the impact AS has on things like communication, sleep, gross/fine motor skills, and seizures. This data is used to inform research and trials so that we can ensure meaningful change can be measured with effective therapeutics.
The Angelman Biomarker Outcome Measures (ABOM) consortium was established to be a pre-competitive space to collaborate across AS patient centered organizations, pharmaceutical companies, and both basic and clinical researchers, to determine what symptoms and endpoints, as well as more objective biomarkers, would be best measured to show the most impact after a successful therapeutic. This consortium has been incredibly successful in bringing all stakeholders to the table to collaborate in the most productive way.
FAST has funded over $20,000,000 towards translational research for Angelman syndrome. For more information on specific grants FAST has funded, go here.
The Emergency Care Consortium will provide a global emergency and urgent care hotline. The hotline will be free of charge, available 24-hours a day and seven days a week, and will enable provider-to-provider consultations to manage urgent issues with the appropriate standards directly related to Angelman syndrome, especially seizures. More than 90% of individuals with Angelman syndrome experience seizures which are often difficult to control with traditional seizure medications. The Emergency Care Consortium will be available for provider-to-provider use in July 2021, with clinical experts that truly understand the nuances unique to Angelman syndrome.
Dr. Keung and his team at North Carolina State University will provide the Angelman syndrome research community a set of cell lines that can be used to efficiently model the biology of ICD and UPD, as well as organoids that model the mosaic genotype. This will aim to help understand any potential impact of gene overexpression in these different genotypes.
This grant focuses on the development of a microRNA approach as a potential therapeutic for the treatment of Angelman syndrome. 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 microRNAs as a potential one-and-done treatment option.