Original Articles
Molecular Therapy (2006) 13, 538–547; doi: 10.1016/j.ymthe.2005.11.008
CNS-Directed AAV2-Mediated Gene Therapy Ameliorates Functional Deficits in a Murine Model of Infantile Neuronal Ceroid Lipofuscinosis
Megan A. Griffey1, David Wozniak2, Michael Wong3, Ellen Bible4, Kendra Johnson2, Steven M. Rothman3, Annie E. Wentz1, Jonathan D. Cooper4 and Mark S. Sands1,5
- 1Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
- 2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
- 3Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
- 4Institute of Psychiatry, Department of Neuroscience, King's College London, London SE5 8AF, UK
- 5Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
Correspondence: Mark S. Sands, Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Fax: +1 314 362 9333. E-mail: msands@im.wustl.edu
Received 26 July 2005; Revised 31 October 2005; Accepted 2 November 2005.
Abstract
The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells, visual defects, seizures, cognitive deficits, and premature death. Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset (
1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Currently there is no effective treatment for children with INCL. In this study, newborn PPT1-deficient mice received two (cortex), four (cortex and hippocampus), or six (cortex, hippocampus, and cerebellum) bilateral intracranial injections of AAV2-PPT1. The AAV-treated animals had localized increases in PPT1 activity, decreased autofluorescent material, improved histologic parameters, and increased brain mass. In addition, the treated animals had dose-dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings. However, there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections. These data suggest that early treatment of INCL using gene transfer techniques can be efficacious. However, higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease.
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RESEARCH
CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosisNature Genetics Letter (01 Jul 1998)
AAV2-mediated Ocular Gene Therapy for Infantile Neuronal Ceroid LipofuscinosisMolecular Therapy Original Article
Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhoodNature Medicine Article (01 Apr 2001)
Timing of Therapeutic Intervention Determines Functional and Survival Outcomes in a Mouse Model of Late Infantile Batten DiseaseMolecular Therapy Original Article
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