Antisense oligonucleotide therapy for neurodegenerative disease
Richard A. Smith, … , C. Frank Bennett, Don W. Cleveland
Richard A. Smith, … , C. Frank Bennett, Don W. Cleveland
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2290-2296. https://doi.org/10.1172/JCI25424.
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Research Article Neuroscience

Antisense oligonucleotide therapy for neurodegenerative disease

Abstract

Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

Authors

Richard A. Smith, Timothy M. Miller, Koji Yamanaka, Brett P. Monia, Thomas P. Condon, Gene Hung, Christian S. Lobsiger, Chris M. Ward, Melissa McAlonis-Downes, Hongbing Wei, Ed V. Wancewicz, C. Frank Bennett, Don W. Cleveland

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Figure 1

Distribution of antisense oligonucleotides after infusion into the right lateral ventricle in rats and Rhesus monkeys.

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Distribution of antisense oligonucleotides after infusion into the right...
(A and B) Antisense oligonucleotides were continuously infused for 2 weeks via infusion pump into the right lateral ventricle of normal rats at 100 μg/d (A) or Rhesus monkeys at 1 mg/d (B). Tissues were collected, and extracts were analyzed for oligonucleotide content by capillary gel electrophoresis. Mean ± SD are shown (n = 6 [A]; 2 [B]). (C–M) A 24-mer modified oligonucleotide, Isis13920, was infused for 2 weeks into the right lateral ventricle at 100 μg/d in rats (C–E) or 1 mg/d in Rhesus monkeys (F–M). After perfusion, distribution of the oligonucleotide was determined by immunohistochemistry using a monoclonal antibody that recognizes the oligonucleotide (C–E, F, H, and J–M) or astrocytes (GFAP; G and I). No oligonucleotide staining was seen in animals infused with saline only (D and H), nor in an animal infused with oligonucleotide but using secondary antibody only (E). Scale bars: 50 μm.