期刊
INTERNATIONAL JOURNAL OF TOXICOLOGY
卷 29, 期 2, 页码 143-156出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/1091581809359206
关键词
Exon skipping; phosphorodiamidate morpholino oligomer; genotoxicity; antisense oligonucleotide; safety pharmacology
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 mg/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.
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