title: Safety pharmacology and genotoxicity evaluation of AVI-4658.
abstract: Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations. Restoration of dystrophin by exon skipping was demonstrated with the phosphorodiamidate morpholino oligomers (PMO) class of splice-switching oligomers, in both mouse and dog disease models. The authors report the results of Good Laboratory Practice-compliant safety pharmacology and genotoxicity evaluations of AVI-4658, a PMO under clinical evaluation for DMD. In cynomolgus monkeys, no test article-related effects were seen on cardiovascular, respiratory, global neurological, renal, or liver parameters at the maximum feasible dose (320 mg/kg). Genotoxicity battery showed that AVI-4658 has no genotoxic potential at up to 5000 microg/mL in an in vitro mammalian chromosome aberration test and a bacterial reverse mutation assay. In the mouse bone marrow erythrocyte micronucleus test, a single intravenous injection up to 2000 mg/kg was generally well tolerated and resulted in no mutagenic potential. These results allowed initiation of systemic clinical trials in DMD patients in the United Kingdom.
authors.affiliation: AVI BioPharma, Bothell, WA, USA. psazani@avibio.com
authors.forename: Peter
authors.initials: P
authors.lastname: Sazani
authors.forename: Doreen L
authors.initials: DL
authors.lastname: Weller
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shrewsbury
mesh_terms: D000818:Animals; D004285:Dogs; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D060172:Morpholinos; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009841:Oligonucleotides / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D060172:Morpholinos; D009153:Mutagens; D009841:Oligonucleotides; C000611335:eteplirsen