Direct image-guided convective perfusion of the bilateral thalami for gene therapy in frontotemporal dementia:...

Certain neurological conditions can be treated by delivering therapeutics to the thalamus, but intrathalamic perfusion properties and methods have not been tested in humans. Therefore, the aim of this study was to define the properties of intrathalamic convective gene therapy delivery by analyzing findings among patients with frontotemporal dementia (FTD) associated with granulin (GRN) mutation who underwent image-guided perfusion of adeno-associated virus serotype 9 (AAV9) expressing GRN.

Consecutive patients with FTD associated with GRN mutations were enrolled in the ASPIRE-FTD clinical trial. Patients underwent real-time MRI-guided convective co-infusion of the bilateral thalami (1200 µL per thalamus divided equally between the anterior and posterior thalami at an infusion rate up to 15 µL/min) with AAV9-GRN and gadolinium-based contrast material (1 mM). Patient and infusion characteristics were assessed.

Three patients (mean age 53.0 ± 18.2 years) underwent a total of 12 thalamic infusions (mean follow-up 6.0 ± 3.0 months). Real-time MRI demonstrated increasing tissue volume of distribution (Vd) with increasing volume of infusion (Vi) (mean Vd-to-Vi ratio of 2.3 ± 0.1, R2 = 0.97). The mean total Vd per side was 2.8 ± 1.4 cm3 (range 2.6-3.2 cm3). The mean thalamic coverage was 39.1% ± 7.5%. Infusion shaping by varying the infusion rate and cannula position permitted excellent intrathalamic distribution (mean perfusion within the thalamus of 87.2% ± 5.4%). There were no surgical complications.

This investigation of real-time MRI-guided convective delivery provided new insights into thalamic gene therapy perfusion properties. The isotropic tissue composition, low propensity for perivascular leakage, and broad interconnectedness make the thalamus an ideal gene therapy target for a wide variety of neurological disorders.