Volume 32

Cover Credit: RNA interference (RNAi) effectors delivered via the adeno-associated virus (AAV) vectors suppress harmful gene variants responsible for dominant disorders, offering therapeutic benefits. In this issue of Gene Therapy, researchers develop an AAV-RNAi strategy targeting neurodevelopmental GNAO1-related disorder characterized by early-onset epilepsy and movement disorders. The image shows iPSC-derived patient-specific neurons expressing a marker of the GABAergic neurotransmission pathway (GABBR1, red; nuclei, blue). The study demonstrates selective downregulation of the pathogenic GNAO1 c.607G>A following AAV-RNAi treatment. However, RNA sequencing analysis revealed safety issues associated with AAV transduction and RNAi activation in neurons.

Cover Credit: AAV-mediated CAS9 delivery to the hippocampus is drastically improved by opening the blood-brain barrier (BBB). Genome editing has an assured place in the future of therapies for diseases of the brain. One major challenge is how to deliver the large editing enzymes such as Cas9. In this issue of Gene Therapy, evidence is presented for dramatic enhancement of viral-mediated delivery through brief and transient opening of the BBB using focused ultrasound. The image shows RNAScope results of Cas9 expression following intrathecal AAV-mediated delivery and opening the BBB of the right but not left hippocampal region.

Cover Credit: Chemogenetic Modulation of Hippocampal Excitability as an Anti-Seizure Strategy. In this issue of Gene Therapy, researchers investigate the use of PSAM4-GlyR-based chemogenetics to modulate neuronal excitability in the hippocampus, the epileptic foci, offering a potential anti-seizure strategy. The study demonstrates that activation of PSAM4-GlyR reduces excitability and seizure susceptibility ex vivo, highlighting its therapeutic potential. The image shows the hippocampi of naive animals on the top, stained for the mossy fiber marker zinc transporter (left) and neuronal marker (right); and chronic epileptic animals treated with intrahippocampal kainic acid (IHKA) at the bottom. Different experimental conditions are separated by a trace showing the electrical brain activity of IHKA animals registered by EEG.

Cover Credit: Created in BioRender. Wheeler, C. (2025) https://BioRender.com/x94u003.