RNA Interference Protects Against Neurodegeneration In Animal Model Of ALS

NEW YORK (Reuters Health) - Using short interfering RNA to silence mutant forms of superoxide dismutase (SOD1) delays the onset and progression of amyotrophic lateral sclerosis (ALS) in a mouse model, according to two papers in the April issue of Nature Medicine.

About 20% of patients with familial ALS have mutations in SOD1. Transgenic mice overexpressing mutant forms of SOD1 develop progressive paralysis resembling ALS disease in humans.

Teams led by Dr. G. Scott Ralph at Oxford Biomedica in the UK and Dr. Patrick Aebischer at Ecole Polytechnique Federale de Lausanne in Switzerland used lentiviral vectors to deliver short hairpin RNA (shRNA) targeting mutant human SOD1 overexpressed by transgenic mice.

When Dr. Ralph's group injected the vector into muscles of the mutant mice, the onset of ALS symptoms was delayed from an average of 94 days in untreated animals to 202 days (p < 0.001). There was a 40% reduction of SOD1 protein levels in the ventral horn tissue of treated mice.

Even though the animals developed weakness and immobility, they never showed severe signs of hind limb dysfunction observed in SOD1 mice, and weight loss was reduced, the authors report. Survival was extended from 128 days to 228 days (p < 0.001).

The primary purpose of the research was to demonstrate the efficacy of vector-based RNAi approaches, Oxford Biomedica CEO Dr. Alan Kingsman told Reuters Health.

"When you inject the delivery vector into muscles, that vector enters the motor neurons that control that muscle via the neuromuscular junction, then the product travels up the nerve fiber to the spine where it treats the body of the cell," he explained.

"When we do these experiments we select a number of muscle groups critical to survival: the diaphragm so they can breathe, the mouth and face muscles so they can eat, and leg muscles so they can walk to their food," Dr. Kingsman continued. If used in humans, "one would need to adopt a strategy where a much broader range of muscle groups would be treated, and you would probably do that over an extended period of time."

He noted that similar technology is being considered for treatment of nonfamilial ALS with vascular endothelial growth factor (see Reuters Health report, May 26, 2004). His group plans to begin clinical trials using lentiviral delivery of VEGF in the near future.

Dr. Aebischer's team observed similar results when they injected the lentiviral vector expressing shRNA targeting SOD1 into the lumbar spinal cord of transgenic mice. Disease onset was delayed by approximately 20 days. Neuromuscular function was improved by 40%, they report, while motor neuron survival was improved by 60%.

This technology may also be beneficial in "other neurodegenerative disorders related to a toxic gain-of-function, such as alpha-synuclein-associated inherited forms of Parkinson disease or Huntington disease," Dr. Aebischer and his associates add.

Source: Nature Med 2005. [ Google search on this article ]

MeSH Headings: Animals, Laboratory : Animals, Transgenic : Biological Therapy : Genetic Engineering : Genetic Techniques : Invertebrates : Mice, Transgenic : Specialty Chemicals and Products : Investigative Techniques : Nucleic Acids, Nucleotides, and Nucleosides : Therapeutics : Gene Therapy : Molecular Probes : Nucleic Acid Probes : Lentivirus : RNA, Antisense : Antisense Elements (Genetics) : Laboratory Chemicals : Chemical Actions and Uses : Organisms, Transgenic : Uses of Chemicals and Drugs : Analytical, Diagnostic and Therapeutic Techniques and Equipment : Chemicals and Drugs

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