Avi Biopharma, Inc.

Sarepta Therapeutics, Inc.

U.S. Army Medical Research and Material Command

The United States of America, As Represented by the Secretary, Department of Health and Human Services

The Scripps Research Institute

Oregon Health & Science University

M.i.t.

The United States of America As Represented by the Army Medical Research and Material Command

US Government As Represented by the Secretary of the Army

David A Stein

Patrick L Iversen

Dwight D Weller

Sina Bavari

Hong M Moulton

Michelle H Nelson

Andrew D Kroeker

Richard Keith Bestwick

Alvin W Smith

Douglas E Skilling

Benjamin Neuman

Michael Buchmeier

Klaus Frueh

Qing Ge

Jianzhu Chen

Cornelis A Rijnbrand

Compositions and methods for enhancing delivery of molecules, e.g. biological agents, into cells are described. The composition is a conjugate of the biological agent, preferably a nucleic acid analog having a substantially uncharged backbone, covalently linked to a peptide transporter moiety as described. Conjugation of the peptide transporter to a substantially uncharged nucleic acid analog, such as a morpholino oligomer, is also shown to enhance binding of the oligomer to its target sequence and enhance antisense activity.

Compositions for enhancing transport of molecules into cells

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Flaviviridae, Picornaviridae, Caliciviridae, Togaviridae, Arteriviridae, Coronaviridae, Astroviridae and Hepeviridae families in the treatment of a viral infection. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with stem-loop secondary structure within the 5'-terminal end 40 bases of the positive-sense RNA strand of the virus.

Antisense antiviral compound and method for treating ss/RNA viral infection

A method of inhibiting replication of a flavivirus in animal cells, and an oligonucleotide compound for use in the method are disclosed. The oligonucleotide analog (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the cells, (iii) contains between 8-40 nucleotide bases, and (iv) has a sequence of at least 8 bases complementary to a region of the virus' positive strand RNA genome that includes at least a portion of SEQ ID NOS:1-4. Exposure of cells infected with a flavivirus to the analog is effective to form within the cells, a heteroduplex structure composed of the virus ssRNA and the oligonucleotide, characterized by a Tof dissociation of at least 45&#xb0; C., and having disrupted base pairing between the virus's 5' and 3&#x2032; cyclization sequences.

Oligonucleotide analog and method for treating flavivirus infections

Pharmaceutical compositions that comprise an siRNA molecule used in the treatment of diseases caused by flavivirus infection and methods of their use are disclosed. The pharmaceutical compositions treat diseases caused by yellow fever virus, West Nile virus, and dengue virus and include a single pharmaceutical composition active against all four dengue virus serotypes.

siRNA useful in the treatment of flavivirus infection

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Flaviviridae, Picornoviridae, Caliciviridae, Togaviridae, Arteriviridae, Coronaviridae, Astroviridae and Hepeviridae families in the treatment of a viral infection. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with stem-loop secondary structure within the 5'-terminal end 40 bases of the positive-sense RNA strand of the virus.

Antisense antiviral compound and method for treating ssRNA viral infection

The invention provides antisense antiviral compounds and methods of their use in inhibition of growth of viruses of the picornavirus, calicivirus, togavirus and flavivirus families, as in treatment of a viral infection. The antisense antiviral compounds have morpholino subunits linked by uncharged phosphorodiamidate linkages interspersed with cationic phosphorodiamidate linkages.

Antisense antiviral agent and method for treating ssRNA viral infection

A method and oligonucleotide compound for inhibiting replication of a nidovirus in virus-infected animal cells are disclosed. The compound (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the infected cells, (iii) contains between 8-25 nucleotide bases, and (iv) has a sequence capable of disrupting base pairing between the transcriptional regulatory sequences in the 5' leader region of the positive-strand viral genome and negative-strand 3&#x2032; subgenomic region. In practicing the method, infected cells are exposed to the compound in an amount effective to inhibit viral replication.

Oligonucleotide compound and method for treating nidovirus infections

A method of inhibiting replication of a flavivirus in animal cells, and an oligonucleotide compound for use in the method are disclosed. The oligonucleotide analog (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the cells, (iii) contains between 8-40 nucleotide bases, and (iv) has a sequence of at least 8 bases complementary to a region of the virus' positive strand RNA genome that includes at least a portion of SEQ ID NOS:1-4. Exposure of cells infected with a flavivirus to the analog is effective to form within the cells, a heteroduplex structure composed of the virus ssRNA and the oligonucleotide, characterized by a Tm of dissociation of at least 45&#xb0; C., and having disrupted base pairing between the virus' 5' and 3&#x2032; cyclization sequences.

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Picornaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment ofand/orinfection in a mammal. The antisense antiviral compounds are substantially uncharged, morpholino oligonucleotides have a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with viral RNA sequences within a 32 nucleotide region of the viral 5' untranslated region identified by SEQ ID NO:7.

Method for treating enterovirus or rhinovirus infection using antisense antiviral compounds

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Orthomyxoviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment of influenza virus infection in a mammal. The antisense antiviral compounds are substantially uncharged morpholino oligonucleotides having 1) a nuclease resistant backbone, 2) 12-40 nucleotide bases, and 3) a targeting sequence of at least 12 bases in length that hybridizes to a target region selected from the following: a) the 5' or 3&#x2032; terminal 25 bases of the negative sense viral RNA segment of Influenzavirus A, Influenzavirus B and Influenzavirus C; b) the terminal 25 bases of the 3&#x2032; terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

Antisense antiviral compound and method for treating influenza viral infection

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Picornaviridae family and in the treatment of a viral infection. The compounds are particularly useful in the treatment ofand/orinfection in a mammal. The antisense antiviral compounds are substantially uncharged, including partially positively charged, morpholino oligonucleotides have a sequence of 12-40 subunits, including at least 12 subunits having a targeting sequence that is complementary to a region associated with viral RNA sequences within a 32 nucleotide region of the viral 5' untranslated region identified by SEQ ID NO:4.

Antisense antiviral compound and method for treating picornavirus infection

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Filoviridae family, and in the treatment of a viral infection. The compounds and methods relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds are morpholino oligonucleotides having: a) a nuclease resistant backbone, b) 15-40 nucleotide bases, and c) a targeting sequence of at least 15 bases in length that hybridizes to a target region selected from the following: i) the Ebola virus AUG start site region of VP24; ii) the Ebola virus AUG start site region of VP35; iii) the Marburg virus AUG start site region of VP24; or iv) the Marburg virus AUG start site region of NP.

Growing community of inventors

Corvallis, OR, United States of America

David A Stein