Developing a CRISPR-activation (CRISPRa) Therapy for the Class I/II Deletion Genotype of Angelman Syndrome
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 expression. In the case of large deletions, which account for the majority of individuals living with AS (~60-70%), not only is UBE3A deleted but an additional 10 or so surrounding genes are also missing from the maternal allele in the 15q11-13 region. Deletion of these genes results in haploinsufficiency, or half the amount that is generally present, and this can contribute to the increased symptom severity seen in those individuals living with the deletion genotype. This project will explore a unique therapeutic avenue that aims to upregulate some of the most important critical genes in this region, outside of UBE3A, looking at them all individually and collectively. They will be evaluated in both a cellular (in vitro) and rodent model (in vivo). 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 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 both in vitro and in vivo. In addition, Dr. Jiang has designed a 2 large deletion AS mouse models (6MB), one with Ube3a expression intact and one with the entire segment of 6MB missing. These models we hope will help to best understand how the loss of these surrounding genes affect mouse behavior relevant to AS. The overarching goal of this project is to understand how upregulating the additional haploinsufficient genes on the paternal allele may lead to therapeutic benefit beyond addressing just the loss of Ube3a.
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 distinct chance to invest in a potential therapy that can target the few additional essential genes beyond UBE3A, which may one day offer an additional treatment option to improve the lives of those living with a large deletion genotype of AS.
Principle Investigator
Nadav Ahituv, PhD
Nadav Ahituv is a Professor in the Department of Bioengineering and Therapeutic Sciences and the Director of the Institute for Human Genetics at the University of California, San Francisco. He received his PhD in human genetics from Tel-Aviv University working on hereditary hearing loss. He then did his postdoc, specializing in functional genomics, in the Lawrence Berkeley National Laboratory and the DOE Joint Genome Institute. His current work is focused on identifying gene regulatory elements and linking nucleotide variation within them to various phenotypes including morphological differences between species, drug response and human disease. His lab was one of the co-developers of massively parallel reporter assays (MPRAs) that allow for high-throughput functional characterization of gene regulatory elements. In addition, he pioneered cis-regulation therapy (CRT), the use of gene regulatory elements as therapeutic targets for haploinsufficient disorders, and adipose modulation transplantation (AMT), a novel cancer cell therapy.
