This week we are going to continue with the focus on FAST’s 4 Pillars in the Roadmap to a Cure 2.0, highlighting Pillar 2 – Fix Dad’s Gene.
To quickly reiterate, everyone has both a mom (maternal) and dad (paternal) copy of UBE3A in the brain and the paternal copy is silenced due to an antisense transcript that binds to the dad’s copy and prevents the process required to produce UBE3A protein. This is fine when the maternal copy can produce functional UBE3A, but in the case of Angelman syndrome where maternal UBE3A does not, a promising approach towards treating AS lies in turning on, or reactivating, paternal UBE3A. This Pillar 2 – Fix Dad’s Gene encompasses all work being done to reactivate the paternal UBE3A copy via antisense knockdown in the brain and in this week’s newsletter we will feature some of the exciting work Dr. Yong-Hui Jiang presented at the 2022 FAST Science Summit.
In his talk, Dr. Jiang discussed a novel CRISPR editing approach packaged in chemically engineered ribonucleoproteins to knockdown the paternal antisense transcript and reinstate paternal expression. In a mouse model of AS, they injected the treatment into the central nervous system (either directly into the brain or through the spine) and observed a clear reactivation of paternal expression, suggesting their therapeutic design was successful in knockdown of the antisense transcript. What’s more, they detected paternal reactivation up to 90 days post treatment with high efficiency in around 76% of neurons. This change in paternal expression resulted in measurable changes in behavior, notably improved performance in both the motor and cognitive domains. Additionally, the treatment resulted in low levels of toxicity evaluated through liver and kidney readouts as well as weight and survival rates.
Given the success of work done so far, Dr. Jiang and his team and currently optimizing human guide RNAs in parallel with their preclinical research. This work is particularly exciting when thinking about transitioning from the bench (research science) to bedside (clinical trials) in that 1. The delivery mechanism proposed is non-viral, suggesting lower immunogenicity and reduced safety concerns and 2. This therapeutic would only require a one-time treatment.
Watch Dr. Jiang’s presentation from the 2022 FAST Global Science Summit to learn more: