With the exception of the glycoprotein gene, all aforementioned genes are monocistronic, which means that they encode for only one structural protein.
A pharmaceutical composition for inhibiting the expression of a gene from an Ebola virus in an organism, comprising a double-stranded ribonucleic acid dsRNA and a lipid formulation comprising the cationic lipid of formula A: The pharmaceutical composition of claim 1, wherein said first sequence is selected from the group consisting of the sense sequences of Table 2 and said second sequence is selected from the group consisting of the antisense sequences of Table 2.
The pharmaceutical composition of claim 1, wherein said dsRNA comprises at least one modified nucleotide.
The pharmaceutical composition of claim 3, wherein said dsRNA comprises at least one modified nucleotide. The pharmaceutical composition of claim 4, wherein said modified nucleotide is chosen from the group of: A method for inhibiting the expression of a gene from an Ebola virus in a cell, the method comprising: A method of treating, preventing or managing pathological processes mediated by Ebola expression comprising administering to a subject in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of the pharmaceutical composition of claim 1.
The pharmaceutical composition of claim 1, wherein said region of complementarity is nucleotides in length. The pharmaceutical composition of claim 1, wherein R1 and R2 of formula A are independently selected from oleoyl, pamitoyl, steroyl, or linoleyl.
The pharmaceutical composition of claim 1, wherein R1 and R2 of formula A are both linoleyl. The pharmaceutical composition of claim 1, wherein R3 and R4 of formula A are methyl. The pharmaceutical composition of claim 1, wherein the cationic lipid of formula A is 2,2-Dilinoleyldimethylaminoethyl-[1,3]-dioxolane.
The pharmaceutical composition of claim 1, further comprising a neutral lipid, a sterol, a PEG, or a PEG-modified lipid. The pharmaceutical composition of claim 20, wherein said pharmaceutical composition comprises LNP The pharmaceutical composition of claim 20, wherein said pharmaceutical composition comprises Formulation M.
A method of increasing life-span of, decreasing viral titre in, or sustaining platelet count in a subject infected with an Ebola virus, comprising administering to the subject the pharmaceutical composition of claim 1 in an amount sufficient to increase the life-span of, decreasing viral titre in, or sustaining platelet count in the subject.
A pharmaceutical composition for inhibiting the expression of a gene from an Ebola virus in an organism, comprising a double-stranded ribonucleic acid dsRNA and a lipid formulation comprising a compound of formula X, selected from the group consisting of: The government has certain rights in the invention.
The sequence listing is incorporated by reference. In humans the diseases caused by these viruses include influenza Orthomyxoviridaemumps, measles, upper and lower respiratory tract disease Paramyxoviridaerabies Rhabdoviridaehemorrhagic fever Filoviridae, Bunyaviridae and Arenaviridaeencephalitis Bunyaviridae and neurological illness Bomaviridae.
Virtually the entire human population is thought to be infected by many of these viruses. The Ebola virus comes from the Filoviridae family, similar to the Marburg virus.
Of identified cases, there were deaths. Ina second, similar virus was identified in Reston, Va. Of around identified human Ebola infections, two-thirds of the patients have died. The animal or other reservoir which sustains the virus between outbreaks has not been identified. Among humans, the Ebola virus is transmitted by direct contact with infected body fluids such as blood.
The incubation period of Ebola hemorrhagic fever varies from two days to four weeks. Symptoms are variable too, but the onset is usually sudden and characterised by high fever, prostration, myalgia, arthralgia, abdominal pains and headache.
These symptoms progress to vomiting, diarrhea, oropharyngeal lesions, conjunctivitis, organ damage notably the kidney and liver by co-localized necrosis, proteinuria, and bleeding both internal and external, commonly through the gastrointestinal tract.
Death or recovery to convalescence occurs within six to ten days of onset of symptomology. The development of a successful therapeutic for Ebola virus is a long-sought and seemingly difficult endeavor. Although they cause only a few hundred deaths worldwide each year, filoviruses are considered a significant world health threat and have many of the characteristics commonly associated with biological weapons since they can be grown in large quantities, can be fairly stable, are highly infectious as an aerosol, and are exceptionally deadly.
Administration of type I interferons, therapeutic vaccines, immune globulins, ribavirin, and other nucleoside analogues have been somewhat successful in rodent Ebola virus models, but not in nonhuman primate infection models.
This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene. Recent reports have indicated that in vitro, RNAi may show some promising in reducing Ebola replication and providing protection in guinea pigs Geisbert, et al.
However, the RNAi agents examined were not designed against all known Ebola strains and were not selected for stability and other properties needed for in vivo therapeutic RNAi agents.
Accordingly, despite significant advances in the field of RNAi, there remains a need for an agent that can selectively and efficiently silence a gene in the Ebola virus using the cell's own RNAi machinery that has both high biological activity and in vivo stability, and that can effectively inhibit replication of the Ebola virus for use in treating pathological processes mediated by Ebola infection.
The invention also provides compositions and methods for treating pathological conditions and diseases caused by Ebola viral infection, such as systemic hemorrhage and multi-organ failure.A comparative study of strains of Ebola virus isolated from southern Sudan and not display all of the characteristics of tages in that this species is widely used in northern Zaire in J.
Med. Leroy EM, Baize S, Mavoungou E, Apetrei C (a) Sequence analysis of the GP, NP, VP40 and VP24 genes of Ebola virus isolated from deceased, surviving and asymptomatically infected individuals during the outbreak in Gabon: comparative studies and phylogenetic characterization.
There are five antigenically distinct ebolaviruses that cause hemorrhagic fever in humans or non-human primates (Ebola virus, Sudan virus, Reston virus, Tai Forest virus, and Bundibugyo virus).
The small handful of antibodies known to neutralize the ebolaviruses bind to the surface glycoprotein termed GP1,2. However, the case fatality rate was below 50% in this outbreak, compared to % found in earlier outbreaks caused by other Ebola virus strains, like Zaire ebolavirus.
1 1 MacNeil A, Farnon EC, Morgan OW, et al. Filovirus Outbreak Detection and Surveillance: Lessons from Bundibugyo [PDF – KB]. Ebola, also known as Ebola hemorrhagic fever or Ebola viral disease, is a rare and deadly illness caused by one of the strains of Ebola virus.
The filoviruses, Ebola (EBOV) and Marburg (MARV), cause a lethal hemorrhagic fever. Human isolates of MARV are not lethal to immmunocompetent adult mice and, to date, there are no reports of a mouse-adapted MARV model. Previously, a uniformly lethal EBOV-Zaire mouse-adapted virus was developed by. With a new outbreak reported in the Democratic Republic of Congo (DRC) in May , the Ebola virus is again in the news; four years have passed since the emergence of a major epidemic in West. Apr 23, · The present invention provides compositions comprising therapeutic nucleic acids (e.g., interfering RNA such as siRNA) that target Ebola virus (EBOV) gene expression and methods of using such compositions to silence EBOV gene expression.
This viral agent is regarded as a prototype pathogen. Over the past four decades, Ebola virus infections are reported periodically, but, as far as the mortality is concerned, early s outbreak was the most worst and reported in Congo, Sudan, Uganda, Gabon and Congo-Brazzaville.