Trial reportThe Lancet. Neurology2013
An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study.
Trial report in The Lancet. Neurology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT01041222 (A Phase 1, Double-Blind, Placebo-Controlled, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of ISIS 333611 Administered Intrathecally to Patients With Familial Amyotrophic Lateral Sclerosis Due to Superoxide Dismutase 1 Gene Mutations), which is not on this map. Cited by 305 papers, 3 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 1, Double-Blind, Placebo-Controlled, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of ISIS 333611 Administered Intrathecally to Patients With Familial Amyotrophic Lateral Sclerosis Due to Superoxide Dismutase 1 Gene Mutations
Who cites it
305 citing papers in PubMed, 3 syntheses or guidelines pooled it, 603 citations in OpenAlex.
- The NGS technology for the identification of genes associated with the ALS. A systematic review.European journal of clinical investigation · 2020Pooled it
- Metabolic Alteration and Amyotrophic Lateral Sclerosis Outcome: A Systematic Review.Frontiers in neurology · 2019Pooled it
- Assisted delivery of antisense therapeutics in animal models of heritable neurodegenerative and neuromuscular disorders: a systematic review and meta-analysis.Scientific reports · 2018Pooled it
- Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease.Clinical and translational science · 2021Trial
- Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?The pharmacogenomics journal · 2020Trial
- Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressiveNeurology · 2018Trial
- From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1 Gene-Associated Amyotrophic Lateral Sclerosis.Mayo Clinic proceedings. Innovations, quality & outcomes · 2026Article
- i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1Molecular therapy. Advances · 2026Article
- Meta-analysis of adverse events in clinical studies with antisense oligonucleotide therapies.Molecular therapy. Nucleic acids · 2026Review
- Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.Journal of extracellular vesicles · 2026Article
- snoRNAs and their derived sdRNAs: Emerging regulators, biomarkers, and therapeutic targets in human cancers (Review).International journal of oncology · 2026Review
- Gene Targeted Therapies for Neurodegenerative Disorders: Strategies and Implications in ALS and SMA.Genes · 2026Review
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.Drug design, development and therapy · 2026Review
- Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.Stem cell research & therapy · 2025Review
- SOD1, A Crucial Protein for Neural Biochemistry: Dysfunction and Risk of Amyotrophic Lateral Sclerosis.Molecular neurobiology · 2025Review
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Improving IL12 immunotherapy in glioblastoma by targeting the long noncoding RNA INCR1.Journal of neuro-oncology · 2025Article
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
245 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on by
- Erratum issued
Authors and funding
20 authors at 8 institutions in 1 country.
Funding
Abstract
backgroundMutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis.
methodsIn this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222.
findingsSeven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated.
interpretationThis trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders.
fundingThe ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.