Towards a Genetic Therapeutic for DEAF1-Associated Neurodevelopmental Disorder (DAND)

It is estimated that 30-80% of neuro-developmental and -psychiatric disorders occur through genetic alterations. More specifically, de novo autosomal dominant mutations likely account for 20-60% of intellectual disability cases. Studies have identified mutations in the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) in individuals with neurodevelopmental disorders. These affected individuals also have a number of similar developmental delays including autism spectrum disorder (ASD). This condition is collectively termed DEAF1-associated  neurodevelopmental disorders (DAND). DEAF1 is a high confidence SFARI autism risk gene (score 1), listed as an autism associated gene (156 total genes) in “The SPARK Gene List”, and is shown in several studies as a top gene implicated in risk for ASD. The long-term research objective of Dr. Jensik’s group is to characterize the roles of DEAF1 in cognitive development, and the mechanisms by which DEAF1 mutations cause DAND. Given their recent success and insights from a project aimed to develop a genetic therapeutic that targets the mutant gene in Huntington’s disease, they have expanded their long-term research objectives to explore the development and use of genetic therapeutics for DAND. Unfortunately, pharmaceutical treatments, which usually only attempt to alleviate symptoms, are lacking for DAND as well. More importantly there is a critical need to address the underlying genetic problem causing DAND. Fortunately, the number of genetic therapeutic clinical trials that make use of adeno-associated virus (AAV) as a delivery system to target specific genes that cause ASD, developmental disorders, and other central nervous system genetic disorders continue to increase. Research and optimization in the use of AAV delivery systems as genetic therapeutics is quickly progressing forward to overcome previous obstacles including dosage, immune response, and the ability of AAV to pass through the human blood-brain barrier. Several studies have shown positive outcomes using AAV delivered genetic therapeutics for Rett, Fragile X, and Angelman syndromes. The goal of this project is to 1) develop and optimize a single AAV based knockdown/replacement system that will target all of the identified (~60) human DEAF1 variants, 2) determine a “therapeutic window” for DEAF1 replacement in DEAF1 deficient mice and 3) test a knockdown/replacement system in 2 different genotype appropriate DAND mouse models. The data obtained will set the foundation for new collaborations and studies aimed to move this potential genetic therapeutic to the next stages of drug testing.