Title | Effective gene therapy for an inherited CNS disease in a large animal model. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Vite CH, McGowan JC, Niogi SN, Passini MA, Drobatz KJ, Haskins ME, Wolfe JH |
Journal | Ann Neurol |
Volume | 57 |
Issue | 3 |
Pagination | 355-64 |
Date Published | 2005 Mar |
ISSN | 0364-5134 |
Keywords | alpha-Mannosidase, Animals, Animals, Genetically Modified, Brain, Brain Mapping, Cats, Disease Models, Animal, Genetic Therapy, Genetic Vectors, Glycogen Storage Disease Type II, In Situ Hybridization, Injections, Magnetic Resonance Imaging, Neurologic Examination, RNA, Messenger, Staining and Labeling, Time Factors, Transduction, Genetic, Treatment Outcome |
Abstract | Genetic diseases affecting the brain typically have widespread lesions that require global correction. Lysosomal storage diseases are good candidates for central nervous system gene therapy, because active enzyme from genetically corrected cells can be secreted and taken up by surrounding diseased cells, and only small amounts of enzyme (<5% of normal) are required to reverse storage lesions. Injection of gene transfer vectors into multiple sites in the mouse brain has been shown to mediate widespread reversal of storage lesions in several disease models. To study a brain closer in size to the human brain, we evaluated the extent of storage correction mediated by a limited number of adeno-associated virus vector injections in the cat model of human alpha-mannosidosis. The treated cats showed remarkable improvements in clinical neurological signs and in brain myelination assessed by quantitative magnetic resonance imaging. Postmortem examination showed that storage lesions were greatly reduced throughout the brain, even though gene transfer was limited to the areas surrounding the injection tracks. The data demonstrate that widespread improvement of neuropathology in a large mammalian brain can be achieved using multiple injection sites during one operation and suggest that this could be an effective treatment for the central nervous system component of human lysosomal enzyme deficiencies. |
DOI | 10.1002/ana.20392 |
Alternate Journal | Ann Neurol |
PubMed ID | 15732095 |
Grant List | DK 07748 / DK / NIDDK NIH HHS / United States RR 02512 / RR / NCRR NIH HHS / United States R01 NS038690 / NS / NINDS NIH HHS / United States DK 47747 / DK / NIDDK NIH HHS / United States R01 DK063973 / DK / NIDDK NIH HHS / United States NS 38690 / NS / NINDS NIH HHS / United States K08 NS 02032 / NS / NINDS NIH HHS / United States P40 OD010939 / OD / NIH HHS / United States DK 63973 / DK / NIDDK NIH HHS / United States |
Related Institute:
Brain Health Imaging Institute (BHII)