title: Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates.
abstract: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD).
  
  
  
  Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here.
  
  
  
  PMOs were administered once-weekly by bolus intravenous (IV) injections to male NHPs. Endpoints evaluated included plasma exposures, clinical observations, body weight/food consumption, eye exams, electrocardiograms, male reproductive hormones/endpoints, complement alternative pathway, clinical pathology, urinalysis, and macroscopic/light microscopic pathology.
  
  
  
  Findings in these studies were limited to the kidneys, with a common presentation of tubular basophilia, vacuolation, and/or minimal degeneration that was considered non-adverse. No necrosis, glomerular lesions, or effects on renal function tests such as serum creatinine or urea nitrogen were observed, suggesting that PMO-related kidney findings are not likely to develop into frank nephrotoxicity. There were no adverse effects on other potential target organs after repeated IV injections at the highest dose levels tested, 320 mg/kg.
  
  
  
  Nonclinical results in NHPs for these three PMOs, together with the excellent clinical safety established for eteplirsen to date, suggest that once-weekly IV administration of PMOs for lifetime durations at therapeutic doses will be well tolerated by patients with DMD.
authors.affiliation: R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Carver
authors.affiliation: R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Charleston
authors.affiliation: R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Shanks
authors.affiliation: R&D Pharmacology/Toxicology, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Covance Laboratories, Inc., Madison, WI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mense
authors.affiliation: Covance Laboratories, Inc., Madison, WI, USA.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Covance Laboratories, Inc., Madison, WI, USA.
authors.forename: Harjeet
authors.initials: H
authors.lastname: Kaur
authors.affiliation: Research and Innovation, Sarepta Therapeutics, Inc., Cambridge, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
mesh_terms: D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D004562:Electrocardiography; D005091:Exons; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D060172:Morpholinos / Q000633:toxicity*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology
chemical_list: D060172:Morpholinos; C000611335:eteplirsen
keywords: AVI-4658; Duchenne muscular dystrophy; eteplirsen; exon skipping; kidney toxicity; non-human primates; phosphorodiamidate morpholino oligomers; splice switching oligonucleotides; toxicity studies