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Genetic Medicine

Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations.

Publication Type	Academic Article
Authors	Souweidane M, Fraser J, Arkin L, Sondhi D, Hackett N, Kaminsky S, Heier L, Kosofsky B, Worgall S, Crystal R, Kaplitt M
Journal	J Neurosurg Pediatr
Volume	6
Issue	2
Pagination	115-22
Date Published	08/01/2010
ISSN	1933-0715
Keywords	Aminopeptidases, Brain, Dependovirus, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gene Transfer Techniques, Genetic Therapy, Neuronal Ceroid-Lipofuscinoses, Serine Proteases
Abstract	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.
DOI	10.3171/2010.4.PEDS09507
PubMed ID	20672930
PubMed Central ID	PMC3763702