236 Bilateral Intrathalamic Infusion of rAAVrh8-Hexa/Hexb in a Phase 1/2 Clinical Trial for Gene Therapy in Infantile and Juvenile Tay-Sachs and Sandhoff Disease; Surgical Technique

Abstract

INTRODUCTION: Tay-Sachs (TSD) and Sandhoff (SD) diseases are rare,monogenic and severe neurodegenerative disorders due to Hexosaminidase A deficiency. We performed the first-in-human bilateral thalamic (BiTh) delivery of rAAVrh8-HEXA/HEXB in 8 children in a Phase 1/2 clinical trial. METHODS: Stereotactic infusion cannula placement was performed using ROSA robotic platform. Bilateral trajectories were planned via the trans-frontal route..Head stabilization was accomplished using radiolucent horse-shoe head rest and radiolucent pin-skull clamps. Flexible infusion cannulas were placed through small drill holes using ROSA guidance. Cannula stabilization was achieved using a construct which combined the Navigus brain biopsy platform and flexible cannula bolt. Insertion accuracy was verified with intraoperative CT images. Patients received one of the three doses in each thalamus: 180 mcl (5.87E + 12vg), 360 mcl (1.17E + 13vg) or 720 mcl (2.35E + 13vg). Drug infusion rate was 4 mcl/minute and completed in 90-360 minutes depending on drug dosage. RESULTS: Eight patients received treatment; 5 infants (6, 11, 13, 17, and 20 months) and 3 juvenile (5, 6, 12 years). Duration of follow up was 2-28 months. Outcome assessments included safety, CSF biochemistry, MRI/MRS/DTI, and neurodevelopmental observations. Surgery and drug infusions were well-tolerated. Post-infusion MRIs showed signal enhancement volume coverage in thalamus from 8%-44% parallel to escalating doses. The only surgery related complication was superficial wound dehiscence in two patients. Infants showed partial stabilization or improvement, including in oral feeding and myelination. In juveniles, dystonic posturing worsened after dosing in all 3 patients treated. Two patients died much later from reasons unrelated to surgery or drug infusion. CONCLUSIONS: Surgery for BiTh infusion of rAAVrh8-HEXA/HEXB for gene therapy in infants with TSD and SD is well-tolerated. Patients respond well to treatment with some stabilization or improvement.