New publication investigates a potential downstream therapeutic approach in a mouse model of Angelman syndrome

This week we are highlighting an interesting publication from Drs. Kiyoshi Egawa and Miho Watanabe from the Hokkaido University Graduate School of Medicine and Hamamatsu University School of Medicine, respectively, investigating a potential downstream therapeutic approach in a mouse model of Angelman syndrome – which falls under Pillar 3 of our Roadmap to a Cure.

As a quick reminder, when we discuss downstream therapeutic approaches, we use this phrase to encompass all research focused on addressing the pathways and processes affected by the loss of the UBE3A protein, rather than the loss of the gene itself. In this way, a downstream therapeutic is less specific, as it does not fix the loss of functional UBE3A protein, and therefore does not address every one of the numerous functions the UBE3A protein has. In this paper, researchers assessed how the loss of the mouse Ube3a protein affects the expression of cation-chloride cotransporters, a common mechanism underlying neurodevelopmental disorders when this electrolyte exchange at the cellular level is imbalanced.

Cation-chloride cotransporters help to maintain the concentration of the electrolytechloride (Cl-) in the brain and body. In the brain, this is particularly important as Cl- helps neurons to communicate and function. Therefore, dysregulation of Cl- leads to neurological dysfunction and this research aimed to understand if the loss of the Ube3a protein affects the expression of these transporters, thus proving to be a possible therapeutic approach in the future. There are many therapeutics out there already that control chloride transport, some of which are already approved, therefore understanding if there could be an impact on Angelman syndrome is very important.

In this paper, the researchers found that the expression of these transporters were dysregulated in the Angelman syndrome mouse, particularly in parts of the brain like the hippocampus. The hippocampus is an important brain region as it is associated with learning and memory. In addition, they found that this dysregulation impacted tonic inhibition, which is linked to seizures. To test if addressing the cation-chloride cotransporter expression imbalance could alleviate AS-related behaviors in a mouse model, Bumetanide (a neuronal K+-Cl- cotransporter 1 inhibitor) was administered via a pump for continual administration. Following treatment with Bumetanide, mice lacking functional Ube3a protein exhibited cognitive improvements as well as a reduction in seizure susceptibility. Given these results, treating the cation-chloride cotransporter expression imbalance may be a promising therapeutic approach for addressing the downstream effects of the loss of UBE3A protein in individuals living with Angelman syndrome and further exploration is warranted.

To access the full paper, click on the link here.