Abstract
There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates.
Highlights
Ebola virus (EBOV) and Marburg virus (MARV) are negative-sense, single stranded RNA viruses of the family Filoviridae that cause severe hemorrhagic fever resulting in high lethality
The overall discovery and development strategy involved assessment of Phosphorodiamidate Morpholino Oligomers (PMOs) drug candidates that were designed to bind to viral RNA
They were synthesized corresponding to known gene sequences of Ebola virus for L, VP24, VP30, GP, VP40, VP35, NP and flanking “leader” genome targets
Summary
Ebola virus (EBOV) and Marburg virus (MARV) are negative-sense, single stranded RNA viruses of the family Filoviridae that cause severe hemorrhagic fever resulting in high lethality. The PPMO have been successful in targeting a variety of viruses in animal challenge models including Ebola virus [46,47], coxsackievirus B3 [48], influenza A virus [49, 50], alphaviruses [51], and picornaviruses [52]. Other modification such as the linkage between bases incorporating a limited number (between 2 and 5) of positive charges (PMOplus) leads to enhanced efficacy and improved binding kinetics [47,53].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
