Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations.
OBJECTIVE
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.
Souweidane
Mark M
MM
Department of Neurological Surgery, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA. mmsouwei@med.cornell.edu
Fraser
Justin F
JF
Arkin
Lisa M
LM
Sondhi
Dolan
D
Hackett
Neil R
NR
Kaminsky
Stephen M
SM
Heier
Linda
L
Kosofsky
Barry E
BE
Worgall
Stefan
S
Crystal
Ronald G
RG
Kaplitt
Michael G
MG
D000626:Aminopeptidases / Q000235:genetics*; D001284:Atrophy; D001921:Brain / Q000601:surgery*; D002648:Child; D000229:Dependovirus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D004867:Equipment Design; D005625:Frontal Lobe / Q000473:pathology / Q000601:surgery; D018014:Gene Transfer Techniques / Q000295:instrumentation; D015316:Genetic Therapy / Q000295:instrumentation; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000295:instrumentation; D007267:Injections; D008279:Magnetic Resonance Imaging / Q000295:instrumentation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000473:pathology / Q000601:surgery*; D038361:Neuronavigation / Q000295:instrumentation; D010296:Parietal Lobe / Q000473:pathology / Q000601:surgery; D011183:Postoperative Complications / Q000175:diagnosis; D057057:Serine Proteases / Q000235:genetics*; D014207:Trephining / Q000295:instrumentation / Q000379:methods; D000091346:Tripeptidyl-Peptidase 1
D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human