An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study
Open accessAbstract
BACKGROUND: Mutations 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. METHODS: In 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. FINDINGS: Seven 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. INTERPRETATION: This 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. FUNDING: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
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ASO injection is a current standard of care for spinal muscular atrophy and is in five ongoing Phase I trials in ALS, Parkinson's, and Alzheimer's diseases and in Phase III trials for inherited ALS and Huntington's disease.
“ASO injection is a current standard of care for the fatal childhood disease spinal muscular atrophy15 and is in five ongoing Phase I trials in ALS, Parkinson’s, and Alzheimer’s diseases and in Phase III trials for inherited ALS from a mutation in superoxide dismutase16,17 and for Huntington’s disease18.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [16]
The citation is attached to the claim about Phase III trials for inherited SOD1 ALS. The cited paper instead describes its SOD1 ALS study as a randomised Phase I trial (Abstract, Methods), and the Introduction calls it a first-in-human study. It does not establish the claimed Phase III status. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredAdministering SOD1 ASOs into the CNS of human ALS patients via the CSF has been well tolerated.
“Administering SOD1 ASOs into the CNS of human ALS patients via the CSF has been well tolerated (22).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [22]
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- Authors
- Miller, T. M., Pestronk, A., David, W., Rothstein, J., Simpson, E., Appel, S. H., Andres, P. L., Mahoney, K., Allred, P., Alexander, K., Ostrow, L. W., Schoenfeld, D., Macklin, E. A., Norris, D. A., Manousakis, G., Crisp, M., Smith, R., Bennett, C. F., Bishop, K. M., & Cudkowicz, M. E.
- Affiliations
- Washington University in St. Louis (US)
- Harvard University (US)
- Johns Hopkins University (US)
- Houston Methodist (US)
- Ionis Pharmaceuticals (United States) (US)
- Center for Neurologic Study (US)
- Corresponding author
- Miller, Timothy M
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 12
- Issue
- 5
- Pages
- 435-442
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC3712285
- OpenAlex
- W2128768698
- Cited by
- 617
- References
- 2
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 39 · 2023: 39 · 2022: 35 · 2021: 42 · 2020: 62 · 2019: 57 · 2018: 66 · 2017: 62 · 2016: 63 · 2015: 51 · 2014: 41 · 2013: 25
- FWCI
- 38.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Neurology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- ALS Association
- Muscular Dystrophy Association
- National Institutes of Health (K08NS074194, R01NS078398)
- National Center for Advancing Translational Sciences
- Institute of Clinical and Translational Sciences (UL1 TR000448)
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- SOD1, antisense oligonucleotides, intrathecal drug delivery, gene silencing, safety and tolerability, pharmacokinetics, spinal cord
- MeSH terms
- Superoxide Dismutase-1, Adult, Amyotrophic Lateral Sclerosis, Double-Blind Method, Female, Humans, Injections, Spinal, Male, Middle Aged, Superoxide Dismutase, Treatment Outcome, Oligodeoxyribonucleotides, Antisense
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