MR-Guidance of Gene Therapy for Brain Diseases: Moving From Palliative Treatment to Cures

Abstract

Regulatory bodies in the U.S. and Europe recently approved a gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency, a rare neurologic disorder where a genetic mutation prevents dopamine production in the brain. Affected children fail to develop normal motor and cognitive functions. MRI-guided intraparenchymal delivery of AADC gene therapy to localized gray matter regions-specifically the substantia nigra and ventral tegmental area-has enabled the brain to produce dopamine, resulting in dramatic improvements in physical and cognitive outcomes. The need to target only a small brain region simplifies the surgical approach. However, gene therapy for broader neurodegenerative conditions has progressed more slowly than expected, despite significant global investment. Clinical efficacy depends heavily on the accurate delivery of gene therapeutics via direct brain infusion, cerebrospinal fluid (CSF) administration, or both. Inadequate image guidance during clinical trials makes it difficult to distinguish between true drug inefficacy and delivery failure. We highlight how increasing use of MRI for pre-surgical simulation and real-time therapy monitoring is accelerating gene therapy development for neurological diseases. This manuscript explores MRI's role in guiding intraparenchymal gene delivery, particularly using Convection Enhanced Delivery (CED). MRI contributes across the treatment timeline-from pre-surgical planning and infusion guidance to validating therapeutic coverage. We describe how MRI supports controlled therapeutic distribution for localized treatments and its potential to enable broader distributions needed for correcting widespread genetic anomalies. We also detail how structural and anatomical MRI sequences (T1, T2, Time of Flight, and Diffusion Tensor Imaging (DTI)) can help model likely infusion distributions. Finally, we provide an outlook on how advanced DTI-based algorithms and poroelastic theory could further improve modeling of infusion dynamics. Current MRI-based technologies can be integrated and enhanced to improve CED effectiveness, especially in very young pediatric patients. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 4.