893. Second Generation Gene Therapy Vector for Classical Late Infantile Neuronal Ceroid Lipofuscinosis

• Published in: Molecular therapy Vol. 13; no. S1; p. S344
• Main Authors: Cabrera-Salazar, Mario A., Hodges, Bradley L., Yew, Nelson S., Bu, Jie, Fidler, Jonathan A., Roskelley, Eric M., Scheule, Ronald K., Sleat, David E., Lobel, Peter, Cheng, Seng H., Passini, Marco A.
• Format: Journal Article
• Language: English
• Published: Milwaukee Elsevier Limited 01.05.2006
• Subjects: Enzymes; Gene therapy; Nervous system; Neurosciences; Respiratory failure; Spinal cord; Vectors (Biology); Ventilation
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2006.08.982

Classical late infantile neuronal ceroid lipofuscinosis (cLINCL) is a neurodegenerative disorder that results from the loss of tripeptidyl peptidase I (TPP1) enzyme activity. Patients with cLINCL possess seizures that are frequently associated with blindness, exhibit cognitive and behavioral deficits that are progressive, and death by 7-20 years of age. Accumulation of autofluorescent storage material is a cardinal feature of the disease, as well as axonal degeneration and loss of cortical neurons. A recent study by our group in a knockout mouse model of cLINCL showed that recombinant AAV2 or AAV5 significantly reduced autofluorescent storage and curvilinear bodies in cells of the brain. Reversal of pathology was restricted to injected and nearby structures at a dose of 2.0 e11 genome copies (gc)/ml. To further evaluate AAV gene therapy, a codon-optimized synthetic human CLN2 cDNA was engineered, packaged into AAV1 capsids (AAV1-hCLN2), concentrated to a high titer (3.3 e12 gc/ml), and injected into the CLN2 (-/-) thalamus of one hemisphere. At 1 month post-injection, brain homogenates of the injection site contained TTP1 enzyme activity that was 15-fold higher than corresponding regions of untreated CLN2 (+/+) mice. TPP1 activity was also observed in the rostral and caudal regions of injected hemisphere, and in the contralateral hemisphere at levels 2-fold higher than CLN2 (+/+) controls. These data demonstrate that the AAV1 vector is capable of producing widespread and high levels of TPP1 activity in vivo. A cohort of 4-week old CLN2 (-/-) mice were then injected with AAV1-hCLN2 into multiple structures of the right (striatum, hippocampus, cerebellum) and left (motor cortex, thalamus, medulla) hemispheres to investigate global reversal of pathology, functional recovery, and extension of lifespan. The results of this experiment including behavioral testing and survival data will be presented.