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 S. David,Jeffrey D. Rothstein,Ericka Simpson,Stanley H. Appel,Patricia L. Andres,Katy Mahoney,Peggy Allred,Katie Alexander,Lyle W. Ostrow,David A. Schoenfeld,Eric A. Macklin,Daniel A. Norris,Georgios Manousakis,Matthew J. Crisp,Richard Smith,C. Frank Bennett,Kathie M. Bishop,Merit Cudkowicz +19 more
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In this paper, the authors evaluated the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis.Abstract:
Summary 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.read more
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Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
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RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform
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TL;DR: It is demonstrated that astrocytes derived from postmortem tissue from both FALS and SALS patients are similarly toxic to motor neurons and that SOD1 is a viable target for SALS, as its knockdown significantly attenuatesAstrocyte-mediated toxicity toward motor neurons.
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Current hypotheses for the underlying biology of amyotrophic lateral sclerosis
TL;DR: It is demonstrated that mutations and pathology associated with the TDP‐43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS, and Convergence of these pathways is likely to mediate disease onset and progression.
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Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Robert G. Miller,Carlayne E. Jackson,E. J. Kasarskis,John D. England,Dallas A. Forshew,Wendy Johnston,Sanjay Kalra,J. S. Katz,Hiroshi Mitsumoto,Jeffrey Rosenfeld,Christen Shoesmith,Michael J. Strong,Susan C. Woolley +12 more
TL;DR: More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS.
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