An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: A phase 1, randomised, first-in-man study

Timothy M. Miller, Alan Pestronk, William David, Jeffrey Rothstein, Ericka Simpson, Stanley H. Appel, Patricia L. Andres, Katy Mahoney, Peggy Allred, Katie Alexander, Lyle W. Ostrow, David Schoenfeld, Eric A. Macklin, Daniel A. Norris, Georgios Manousakis, Matthew Crisp, Richard Smith, C. Frank Bennett, Kathie M. Bishop, Merit E. Cudkowicz

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512 Scopus citations


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, 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.

Original languageEnglish (US)
Pages (from-to)435-442
Number of pages8
JournalThe Lancet Neurology
Issue number5
StatePublished - May 2013

Bibliographical note

Funding Information:
We thank the patients who participated in this study, and their families and carergivers. This trial was funded by the Muscular Dystrophy Association, The ALS Association, and Isis Pharmaceuticals. TMM was supported by National Institute of Neurological Disorders and Stroke (NIH) grants K08NS074194 and R01NS078398 . Clinical studies at Washington University were supported by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 , National Center for Advancing Translational Sciences (NIH). We appreciate the hard work and dedication of many people who contributed to this study: Massachusetts General Hospital Coordinating Center (Kate Jackson, Alex Sherman, Marianne Kearney, Hong Yu, Lauren Schnupp, Bryan Sweet, Jason Walker, Igor Katsovskiy, Ervin Sinani), Massachusetts General Hospital clinical site (Swati Aggarwal, Melanie Majkut, Jennifer Berndt, Darlene Sawicki), Johns Hopkins University School of Medicine (Richard Kimball, Lora Clawson, Kristen Riley), Methodist Neurological Institute (Sharon Halton, Luis Lay), Washington University in St Louis (Julaine Florence, Catherine Siener, Brian Sommerville, Robert Swarm, Leo Wang, Charlie Wulf), Isis Pharmaceuticals (Viola Kam, Jesse Kwoh, Katherine Kwoh, John Madson, Gina McMullin, Dan Schultz). We also thank Robert Brown, Benjamin Brooks, and Don Cleveland for input about clinical study design, the data safety and monitoring board (Walter Bradley, Karl Kieburtz, Carl Leventhal, Michael McDermott, Stephen Reingold), and the many investigators of the Northeast ALS Trials Consortium who referred patients to the study and for Patients Like Me for referrals to Johns Hopkins University.


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