Manipulation of zebrafish embryogenesis by phosphorodiamidate morpholino oligomers indicates minimal non-specific teratogenesis

The incidence of teratogenicity caused by therapeutic agents is a significant concern in drug development. Approaches to screening active agents in drug development tend to be limited by relevance to humans, cost from the large number of animals required for testing and complicated by barriers to drug entry into the test organism. The era post-human, -mouse and -zebrafish genome sequence determination should result in more precise experimental approaches to the evaluation of teratogenic potential. Peer-reviewed publications (204 papers) from independent investigators evaluating phosphorodiamidate morpholino oligomers (PMOs) in functional genomic studies are reviewed. These studies utilized over 47,000 embryos and resulted in 0.3% off-targeted or potential teratogenic effects, while at the same time producing the 74% phenotypic penetrance expected for the targeted gene. This represents a very compelling case for the minimal teratogenic potential of PMO chemistry.