NEW YORK (Reuters Health) - Injection of gene transfer vectors directly into the brain is effective in treating the lysosomal storage disease alpha-mannosidosis (AMD) in a cat model, according to a report in the March Annals of Neurology.
Dr. John H. Wolfe from University of Pennsylvania, Philadelphia, Pennsylvania and colleagues evaluated gene therapy in brains of cats affected with AMD, which in humans is characterized by progressive neurological dysfunction and skeletal abnormalities.
Treated 8-week-old cats received injections of vector into six tracks in each cerebral hemisphere plus one track in each cerebellar hemisphere, the report indicates. Disease progression was similar in treated and untreated cats until 12 to 14 weeks of age.
Beyond 12 to 14 weeks of age, the neurological disease stabilized or improved in every treated cat, the authors report. By 18 weeks of age, treated cats could be distinguished from normal cats only by mild truncal ataxia, intermittent fine head tremor, and a shorter than usual stride.
MRI abnormalities also improved in treated cats, the results indicate, though improvement was less obvious in cerebellar regions.
Postmortem analysis demonstrated messenger RNA for the gene-encoded enzyme up to 2.5 mm from the needle track in both the gray and white matter, the researchers note, and the level of enzyme activity was 4% of that in normal cat brain.
Moreover, the investigators report, messenger RNA for the enzyme was still being produced a year after injection of the vector.
Additional investigation revealed that lysosomal storage in neurons, glia, and endothelial cells had completely resolved up to 4.5 mm from the injection tracks, and no region of the treated cat brain showed lysosomal storage as severe as that found in untreated AMD cats.
“This study shows that somatic gene transfer to the CNS can deliver functioning enzyme directly to deficient brain cells without the high morbidity and mortality rates associated with bone marrow transplantation,” the researchers explain.
“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,” the authors conclude.
Source: Ann Neurol 2005;57:355-364. [ Google search on this article ]
MeSH Headings:Biological Therapy: Genetic Engineering: Genetic Techniques: Investigative Techniques: Therapeutics: Gene Therapy: Lysosomal Storage Diseases, Nervous System: Brain Diseases, Metabolic, Inborn: Analytical, Diagnostic and Therapeutic Techniques and EquipmentCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
