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Updated: May 5, 2026
Direct Intraventricular Delivery of Drugs to the Rodent Central Nervous System
Published on: May 12, 2013
Antisense oligonucleotide therapy for neurodegenerative disease
Richard A Smith1, Timothy M Miller, Koji Yamanaka
1Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA.
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.
Insights
Researchers developed a new antisense oligonucleotide therapy to reduce toxic protein buildup in neurodegenerative diseases. This treatment effectively lowered superoxide dismutase 1 (SOD1) levels and slowed disease progression in a model of amyotrophic lateral sclerosis (ALS).
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Protein misfolding and accumulation drive neurodegenerative disease pathogenesis.
- Targeting gene expression offers a therapeutic strategy for these conditions.
- Antisense oligonucleotides (ASOs) can be modified for CNS delivery.
Purpose of the Study:
- To evaluate the efficacy of intraventricularly infused ASOs for downregulating gene expression in the CNS.
- To investigate the therapeutic potential of ASOs targeting superoxide dismutase 1 (SOD1) in a model of amyotrophic lateral sclerosis (ALS).
Main Methods:
- Modified ASOs were infused intraventricularly in rodents and primates.
- ASOs targeting SOD1 were administered to a mouse model of ALS.
- SOD1 protein and mRNA levels were quantified throughout the CNS.
- Disease progression was monitored in the ALS model.
Main Results:
- Intraventricular ASO infusion led to widespread CNS distribution.
- SOD1 ASOs significantly reduced SOD1 protein and mRNA levels in the brain and spinal cord.
- Early treatment with SOD1 ASOs substantially slowed disease progression in the ALS model.
Conclusions:
- Direct CNS delivery of ASOs is a viable strategy for treating neurodegenerative diseases.
- ASO therapy can effectively downregulate target proteins like SOD1.
- This approach holds promise for treating ALS and other neurodegenerative disorders with known targets.
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