Antisense antiviral compounds and methods for treating a filovirus infection
Inventors
Stein, David A. • Iversen, Patrick L. • Bavari, Sina
Assignees
Sarepta Therapeutics Inc • US Army Medical Research and Development Command
Publication Number
US-7524829-B2
Publication Date
2009-04-28
Expiration Date
2025-10-31
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Abstract
The invention provides antisense antiviral compounds and methods of their use in inhibiting of growth of and treating infection by viruses of the Filoviridae family.
Core Innovation
The invention provides antisense antiviral compounds and methods for their use in inhibiting growth of and treating infection by viruses of the Filoviridae family, including Ebola and Marburg viruses. More specifically, it relates to antisense oligonucleotide compounds for treating viral infections in mammals by targeting viral RNA sequences around the AUG start site of viral genes such as VP35, VP24, VP40, VP30 nucleoprotein, and L polymerase. The compounds are oligonucleotide analogs with nuclease-resistant backbones, typically morpholino-based, having 15-40 nucleotide bases, capable of active uptake by mammalian host cells, and able to form stable heteroduplexes with viral RNA with high melting temperature.
The problem solved by the invention arises from the lack of effective antiviral therapies for infections by (−) strand RNA viruses, particularly members of the Filoviridae family like Ebola and Marburg viruses. These viruses cause severe hemorrhagic fevers with high lethality, and development of therapeutics has been hindered by the difficulty of working with these viruses, lack of effective reagents, and absence of vaccines or antiviral drugs. Standard treatments have been limited to supportive care without direct antiviral efficacy. The invention addresses the need for therapeutic compounds that specifically target viral gene expression to inhibit viral replication and provide effective treatment methods.
Claims Coverage
The patent includes three claims focusing on the antiviral composition and its inventive features.
Antisense morpholino oligomer targeted to Ebola VP35 mRNA AUG start site region
An antiviral composition comprising an antisense morpholino oligomer composed of morpholino subunits linked by phosphorous-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′ exocyclic carbon of an adjacent subunit. The oligomer contains a targeting sequence forming a heteroduplex with a target sequence within the AUG start site region of Ebola VP35 mRNA, with at least 12 contiguous bases from sequences selected among SEQ ID NOS:21 to 26, and inhibiting virus production.
Targeting sequence comprising SEQ ID NO:21
The composition wherein the antisense morpholino oligomer targeting sequence specifically has the sequence of SEQ ID NO:21.
Targeting sequence comprising SEQ ID NO:22
The composition wherein the antisense morpholino oligomer targeting sequence specifically has the sequence of SEQ ID NO:22.
The claims focus on antisense morpholino oligomer compositions targeting specific regions of Ebola VP35 mRNA that inhibit viral replication, with the independent claim covering oligomers targeting the AUG start site region and dependent claims specifying particular sequences.
Stated Advantages
The antisense composition provides highly efficacious therapeutic treatment for lethal Ebola virus infections both in vitro and in vivo in rodents and non-human primates.
The compounds have nuclease-resistant backbones and can be actively taken up by mammalian cells, allowing effective intracellular targeting of viral RNA.
Treatment with the antisense compounds can lead to full protection from lethal Ebola virus challenge and stimulate robust immune responses including T cell and antibody responses.
Use of peptide conjugates or cationic linkages can increase cellular uptake and antisense activity, enhancing therapeutic efficacy.
Documented Applications
Treatment of infections by viruses of the Filoviridae family, including Ebola and Marburg virus infections, in mammals including humans and non-human primates.
Use of antisense morpholino oligomer compositions to inhibit Ebola virus replication in infected cells and animal models.
Combination therapies employing multiple antisense compounds targeting different viral genes for enhanced protection against Ebola virus.
Vaccination methods by pretreating mammalian subjects with antisense compounds and subsequently challenging with virus, preferably attenuated forms.
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