Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations
Mark M Souweidane1, Justin F Fraser, Lisa M Arkin
1Department of Neurological Surgery, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA. mmsouwei@med.cornell.edu
Object:
The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2(CU)hCLN2). The operative technique, radiographic changes, and surgical complications are presented.
Methods:
Ten patients with late infantile neuronal ceroid lipofuscinosis disease each underwent infusion of AAV2(CU)hCLN2 (3 x 10(12) particle units) into 12 distinct cerebral locations (2 depths/bur hole, 75 minutes/infusion, and 2 microl/minute). Innovative surgical techniques were developed to overcome several obstacles for which little or no established techniques were available. Successful infusion relied on preoperative stereotactic planning to optimize a parenchymal target and diffuse administration. Six entry sites, each having 2 depths of injections, were used to reduce operative time and enhance distribution. A low-profile rigid fixation system with 6 integrated holding arms was utilized to perform simultaneous infusions within a practical time frame. Dural sealant with generous irrigation was used to avoid CSF egress with possible subdural hemorrhage or altered stereotactic registration.
Results:
Radiographically demonstrated changes were seen in 39 (65%) of 60 injection sites, confirming localization and infusion. There were no radiographically or clinically defined complications.
Conclusions:
The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.
