Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection
Abstract
Phosphorodiamidate morpholino oligomers (PMO) are uncharged nucleic acid-like molecules designed to inactivate specific gene expression through antisense-based steric hindrance of mRNA translation. PMOs have been well-tolerated and effective in both preclinical testing and human clinical trials. PMOs have been highly successful in knockdown of viral gene expression and replication of acute viral infections. Thus, antisense PMOs represent a promising class of therapeutic agents to combat filoviral infections. Previously, we showed that mice treated with a PMO complementary to a region spanning the start codon of VP24 mRNA were nearly completely protected after lethal Ebola virus challenge. In the present study, we report on the ability of two additional VP24-specific PMOs to reduce cell-free translation of a VP24 reporter, to inhibit replication of EBOV in cultured cells, and to protect mice after lethal challenge. Additionally, chemical modifications of the PMOs, including charge modifications of the backbone and addition of arginine-rich peptide tags, increased the potency and efficacy of the molecules. This work provides a strong foundation for the development and use of novel antisense-based strategies for treating known, emerging, and genetically engineered bioterrorism threats.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2009
- Accession Number
- ADA504592
Entities
People
- Candace Lovejoy
- Dana L. Swenson
- Dwight D. Weller
- Gordon T. Ruthel
- Hong M. Moulton
- Jed N. Hassinger
- Kelly Lyn Warfield
- Patrick L. Iversen
- Robert E. Blouch
- Sina Bavari
- Travis K. Warren
Organizations
- United States Army Medical Research Institute of Infectious Diseases