Developing a CRISPR-activation (CRISPRa) Therapy for the Class I/II Deletion Genotype of Angelman Syndrome

Angelman syndrome (AS) results from the loss of functional UBE3A. In the case of large deletions, which account for the majority of all individuals living with AS (~70%), not only is UBE3A deleted but an additional 10 or so surrounding genes are also missing in the 15q11-13 region. Deletion of these genes results in haploinsufficiency that likely contributes to the increased symptom severity of the deletion genotype and adds to the differences between deletion and non-deletion patients. This project will explore a unique therapeutic avenue that aims to upregulate some of the most important critical genes, outside of UBE3A, looking at them both individually and collectively, and then assess them in cellular and rodent models. This project is a collaboration with Dr. Nadav Ahituv at the University of California, San Francisco, Dr. Albert Keung at North Carolina State University, and Dr. Yong-Hui Jiang at Yale University. Dr. Ahituv is a new investigator in Angelman syndrome and a world expert in CRISPR activation, a tool used to upregulate haploinsufficient genes. Drs. Keung and Jiang are leading AS researchers that have been awarded previous funding to create model systems to evaluate therapeutic candidates for AS. Dr. Keung’s work includes the creation of human stem cells with “landing pads” that control the expression of genes within the 15q11-13 region, thus allowing for research in how the loss of certain genes contribute to symptom severity. Dr. Jiang has designed a large deletion AS mouse model, with Ube3a expression intact, to understand how the loss of surrounding genes affect mouse behavior relevant to AS. The overarching hypothesis of this newly funded study aims to understand how upregulating the additional haploinsufficient genes on the paternal allele may result in therapeutic benefit beyond addressing just the loss of UBE3A. This is important for individuals living with AS that have a deletion genotype as it could address the additional genes that contribute to the symptom severity and bring the deletion phenotype (symptoms) closer to that of the nondeletion individuals.

The work being done here is particularly timely. While there have been significant strides in therapeutic design targeting UBE3A for the treatment of AS for all genotypes, these advancements often overlook the other genes within the 15q11-13 locus that likely play a role in the condition's severity in the largest population of AS, deletion. This presents a distinctive chance to invest in a potential therapy that can target essential genes beyond UBE3A, potentially offering an additional treatment option to improve Angelman syndrome management for the largest affected population.