title: An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA. millert@neuro.wustl.edu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: William
authors.initials: W
authors.lastname: David
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.forename: Ericka
authors.initials: E
authors.lastname: Simpson
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Andres
authors.forename: Katy
authors.initials: K
authors.lastname: Mahoney
authors.forename: Peggy
authors.initials: P
authors.lastname: Allred
authors.forename: Katie
authors.initials: K
authors.lastname: Alexander
authors.forename: Lyle W
authors.initials: LW
authors.lastname: Ostrow
authors.forename: David
authors.initials: D
authors.lastname: Schoenfeld
authors.forename: Eric A
authors.initials: EA
authors.lastname: Macklin
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Norris
authors.forename: Georgios
authors.initials: G
authors.lastname: Manousakis
authors.forename: Matthew
authors.initials: M
authors.lastname: Crisp
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Kathie M
authors.initials: KM
authors.lastname: Bishop
authors.forename: Merit E
authors.initials: ME
authors.lastname: Cudkowicz
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
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