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 3

Antisense oligonucleotides reduce rat SOD1 in vivo.

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Antisense oligonucleotides reduce rat SOD1 in vivo. (A–D) Antisense SOD1...
(A–D) Antisense SOD1 oligonucleotides SODr146192 or SODscrambled were infused for 28 days into the right lateral ventricle of normal rats at 100 μg/d. (A) Endogenous SOD1 mRNA levels from brain and spinal cord regions were measured by quantitative real-time |RT-PCR. Mean ± SD are shown (n = 6). (B) SOD1 and α-tubulin protein levels were analyzed by immunoblotting following infusion. The Coomassie-stained gel at top demonstrates equal loading. (C and D) Protein levels for tubulin and SOD1 were quantified for right cortex, cervical cord, and lumbar cord after infusion as in B. Mean ± SD are shown (n = 6). (E) Antisense oligonucleotides against presenilin 1 or GSK-3β were infused for 2 weeks into the right lateral ventricle of nontransgenic mice, and mRNA levels were measured by quantitative RT-PCR in the right frontal/temporal cortex (n = 6).