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Published on: May 14, 2014
Prescriptive Approach to Convective Perfusion of the Bilateral Thalami for Gene Therapy
Russell R Lonser1,2, J Bradley Elder1,2, Mark A Damante1,2
1Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
Background And Objectives:
Consistent and effective convective perfusion of the thalamus for gene therapy across surgeons and institutions will be critical for therapeutic success. To determine if a systematic infusion approach can ensure reliable and successful delivery across surgeons and centers, we developed and used a systematic perfusion technique with real-time imaging to deliver gene therapy to the bilateral thalami.
Methods:
Consecutive subjects with frontotemporal dementia undergoing convective infusion of adeno-associated virus serotype 9 expressing the granulin gene (coinfused with 1 mM gadolinium) into bilateral thalami at 3 sites internationally were included. Subjects underwent perfusion (infusion rate, 1-15 μL/min) of the anterior and posterior thalami [volume of infusion (Vi), 1200 or 1600 μL per thalamus] using a standardized perfusion protocol. Infusions were monitored using real-time MRI. Clinical and imaging findings were analyzed.
Results:
Six consecutive subjects (mean age, 58.5 ± 6.2 years) received systematic bilateral anterior and posterior thalamic infusions (mean follow-up, 10.4 ± 8.5 months). The mean trajectory length from the rostral to caudal border of the thalamus was 16.9 ± 1.6 mm (range, 14-21 mm). The mean total volume of distribution (Vd) per thalamus was 3.2 ± 0.2 and 4.2 ± 0.6 cm3 (Vi, 1200 and 1600). Real-time MRI demonstrated that Vd increased linearly with increasing Vi (R2 = 0.96). Overall, the mean Vd to Vi ratio was 2.7 ± 0.4 (range, 2.4-3.5). The mean thalamic coverage was 48.7% ± 2.3% and 52.6% ± 6.8% (Vi, 1200 and 1600). Systematic use of the cannula position and increasing infusion rate achieved consistent effective intrathalamic distribution (mean within thalamus perfusion, 72.7% ± 8.3%).
Conclusion:
Systematic convective delivery to the thalamus ensures consistent perfusion and enhances both accessibility and procedural uniformity across surgeons and institutions. This methodology reduces the learning curve for convective perfusion and will permit practitioners to implement the technique more efficiently and effectively.
