MRI-Guided AAV Delivery Expands Targeting for AADC Deficiency

January 28, 2026- Researchers at The Ohio State University have pioneered a real-time, MRI-guided delivery technique for Kebilidi (eladocagene exuparvovec-tneq), an approved AAV2-based gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency, enabling simultaneous targeting of midbrain and brainstem regions in adult nonhuman primates (NHPs) to address both dopamine and serotonin deficiencies. AADC deficiency, caused by mutations in the DDC gene, disrupts the production of these neurotransmitters, leading to developmental delays, cognitive issues, behavioral problems, and movement disorders; while current Kebilidi delivery to the putamen or midbrain restores dopamine, it inadequately reaches serotonin-producing brainstem neurons, limiting cognitive and behavioral benefits. The new method, detailed in “Advancing AADC Deficiency Therapy Through MR-Guided Multisite Delivery of AAV2-hAADC to Dopaminergic and Serotonergic Pathways in the Brainstem” published in Molecular Therapy Advances, uses precise MRI planning to infuse the therapy sequentially into the midbrain and deeper brainstem via a single thin tube, with post-infusion scans confirming consistent coverage of key areas despite individual variability.

In the study, half the NHPs received gene therapy and half saline; treated animals showed significantly higher AADC enzyme levels in targeted dopamine- and serotonin-related regions, with increases extending to connected brain areas based on coverage extent, while cerebrospinal fluid showed no widespread neurotransmitter changes. All animals tolerated the procedure without adverse events, maintaining stable weight, activity, and behavior; transient neurofilament light chain elevations indicated minor insertion trauma, resolving quickly, with mild localized inflammation at injection sites but no body-wide immune response or long-term issues, though low AAV2 antibodies developed in some without impacting efficacy. The researchers concluded that this multi-target approach is safe and tolerable, supporting its potential inclusion in clinical development to restore serotonin signaling and improve cognitive/behavioral outcomes in children with AADC deficiency, where current dopamine-focused therapies fall short.