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: Peter Sazani, Doreen L Weller, Stephen B Shrewsbury
• Journal: International journal of toxicology (Int J Toxicol) 2010 Mar-Apr Vol. 29 Issue 2 Pg. 143-56 ISSN: 1092-874X [Electronic] United States
• PMID: 20110565 (Publication Type: Journal Article)

Chemical References

• Morpholinos
• Mutagens
• Oligonucleotides
• eteplirsen

Topics

• Animals
• Dogs
• Macaca fascicularis
• Male
• Mice
• Morpholinos
• Mutagenicity Tests
• Mutagens (toxicity)
• Oligonucleotides (pharmacology, toxicity)