Intraoperative Features of Real-time Magnetic Resonance Imaging of Multi-site Direct Convective Delivery of Gene Therapy in Huntington's Disease

Introduction: Gene therapy clinical trials for nervous system disorders, including Huntington’s disease (HD), often use real-time magnetic resonance (MR)-imaging of convection enhanced delivery (CED) to monitor target structure infusion with the goal of maximizing target structure coverage. However, intraoperative imaging features of these surgical strategies are not well described.

Methods: Consecutive HD patients undergoing administration of recombinant adeno-associated viral vector serotype 5 expressing microRNA targeting human HTT (rAAV5-miHTT) co-infused with 1 mM gadoteridol into bilateral striatum were included. Maximum infusion volumes were 1000 microliters (2 injections) per putamen and 500 microliters (1 injection) per caudate. Surgical and intraoperative MR-imaging features were analyzed.

Results: Six early manifest HD patients underwent real-time MR-imaging during CED of bilateral striatum using a bilateral trans-frontal approach (36 total infusions; 12 caudate, 24 putamen) at one surgical center. MR-imaging demonstrated progressive volume of distribution (Vd) increasing linearly with increasing volume of infusion (Vi) (mean R2=0.99+/-0.01 caudate; 0.99+/-0.006 anterior putamen; 0.99+/-0.005 posterior putamen). Mean Vd/Vi ratio at infusion completion was similar for the three targets: 2.9+/-0.9 (range, 1.4-4.2) for caudate infusions, 2.8+/-0.7 (1.7-3.6) for anterior putamen and 2.9+/-0.8 (1.6-4.0) for posterior putamen. Targeting accuracy (percent infusion within target) was 35.1 +/- 15.6% (range 13.7–62.4%) for caudate infusions, 45.6 +/- 12.7% (30.9–65.3%) for anterior putamen, 42.5 +/- 8.0% (29.1-56.8%) for posterior putamen. Mean percent target structure infused was 18.3 +/-4.6% (range, 12.4-28.7%) per caudate and 36.5 +/- 6.6% (25.6-46.6%) per putamen. Gadoteridol hyperintensity dissipated in a defined manner after stopping infusion (mean T1/2, 95.3 +/- 37.2 minutes). Anatomically-adjacent white/grey matter structure perfusion occurred via infusion volume expansion past target structure borders in 36/36 (100%) of infusions and low resistance pathways (e.g. perivascular spaces) in 32/36 (89%) of infusions.

Conclusion : In HD patients, gene therapy CED followed definable volume of distribution and target structure coverage patterns. After infusion completion, gadoteridol dissipation occurs in a defined manner for grey and white matter. Additional analysis of imaging data and correlation with clinical outcomes is critical for shaping future clinical trials.