Robot-assisted intrathalamic infusion for gene therapy in young children: surgical considerations

Stereotactic gene therapy in children is challenging due to the fragility of the infant skull and long hours of infusion. The thalamus, an integrative hub for the entire cortex, has been shown to facilitate widespread gene/protein delivery via axonal transport. The aim of this study was to evaluate the safety and accuracy of bilateral thalamic convection-enhanced delivery (CED) of adeno-associated virus (AAV) vectors for GM2 gangliosidoses in children and to assess outcomes based on post-infusion imaging.

This clinical trial enrolled 10 pediatric patients, including 7 infants and toddlers and 3 children ranging in age from 5 to 12 years, who underwent bilateral thalamic rAAVrh8-HEXA/HEXB delivery via CED for GM2 gangliosidoses. The approximate trajectory entered the middle frontal gyrus, lateral to the frontal horn and caudate, passing through the anterior limb of the internal capsule to the thalamus. Injection volumes ranged from 180 μL to 1250 μL at a rate of 4 μL/min. The surgical technique for trajectory planning, cranial stabilization, operating room setup, stereotactic cannula placement, infusion parameters, and gene delivery was reviewed. The accuracy of catheter placement was calculated, and the volume of distribution (Vd) versus the volume of infusate (Vi) based on thalamic signal intensity on MRI was quantified.

Ten children (age range 6 months to 12 years) with GM2 gangliosidosis were included. Twenty infusion cannulas were successfully placed for bilateral thalamic drug delivery. Intrathalamic cannula distance measurements ranged from 12.4 to 15.3 mm, and all the cannula steps were inside the thalamic boundaries to prevent backflow. There were no significant intraoperative complications. The mean targeting error was 1.3 ± 0.8 mm. The calculated volume of thalamic coverage by the infusate signal ranged from 5.9% to 53.3% (mean 26.9% ± 15.5%) in a dose escalating pattern. The Vd/Vi ratio ranged from 0.60 to 2.8 (mean 2.0 ± 0.6), depending on the infusate volume. The diffusate shape was circular to slightly ellipsoid in all patients.

In this study, the surgical technique used in the first in-human intrathalamic drug infusion gene therapy trial in young children with GM2 gangliosidosis was reviewed. The innovative stereotactic setup used robotic surgical assistance and ensured high-precision targeting and secure cannula placement during prolonged infusions, even in infants as young as 6 months of age. Post-infusion MRI confirmed that the infusate remained well contained within the thalamus. The mean Vd/Vi ratio of 2.0 is consistent with the literature. Overall, bilateral thalamic delivery of AAV transgene in children was safe and well tolerated.