Avi Biopharma, Inc.

Sarepta Therapeutics, Inc.

University of Nebraska

U.S. Army Medical Research and Material Command

National Institutes of Health, a Component of the US Dept. of Health & Human Services

The Scripps Research Institute

University of Kansas-ku Medical Center Research Institute

Oregon State 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

Patrick L Iversen

Dwight D Weller

David A Stein

Bruce L Geller

Dan V Mourich

Jed N Hassinger

Thomas R Porter

Hong M Moulton

Robert Hudziak

Lucas D Tilley

Sina Bavari

William H Gmeiner

Alan P Timmins

Andrew D Kroeker

Michelle H Nelson

Richard Keith Bestwick

Jesse D Deere

Frederick Joseph Schnell

Alvin W Smith

Stephen H Bartelmez

Michael Buchmeier

Benjamin Neuman

Douglas E Skilling

Gunnar J Hanson

James E Summerton

David J Hinrichs

Hemant Kumar Roy

Nicholas N Kipshidze

Baozhong Cai

Qing Ge

Jianzhu Chen

Gary D Meyer

Randall E Brand

Vincent H Gattone, Ii

John Enrique Mata

Nikki B Marshall

Cornelis A Rijnbrand

Jason Gatlin

Andrew J Annalora

Eric M Scholar

John E Mata

Nicholas Kipshidze

Hong Mu Moulton

Frederick J Schnell

A modified antisense oligonucleotide of about 10 to about 40 nucleobases is disclosed. The oligonucleotide comprises a targeting sequence having a region complementary to at least one string of three or more identical contiguous nucleobases in a target sequence, wherein the target sequence comprises at least one additional nucleobase compared to the region of the targeting sequence and the at least one additional nucleobase has no complementary nucleobase in the region of the targeting sequence, and wherein the targeting region complementary to the at least one string of three or more identical contiguous nucleobases is internal to the targeting sequence.

Antisense oligomer compounds

Morpholino oligomers containing modified intersubunit linkages and/or terminal groups are provided for use within dsRNA molecules. The oligomers are oligonucleotide analogs containing predetermined sequences of base-pairing moieties. Also provided are such oligomers conjugated to peptide transporter moieties, where the transporters are preferably composed of arginine subunits, or arginine dimers, alternating with neutral amino acid subunits.

DsRNA molecules comprising oligonucleotide analogs having modified intersubunit linkages and/or terminal groups

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

A method and compound for treating skeletal muscle mass deficiency in a human subject are disclosed. The composition is an oligomer of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5' exocyclic carbon of an adjacent subunit, contains between 10-40 nucleotide bases, has a base sequence effective to hybridize to an expression-sensitive region of processed or preprocessed human myostatin RNA transcript, identified, in its processed form, by SEQ ID NO:6, and is capable of uptake by target muscle cells in the subject. In practicing the method, the compound is administered in an amount and at a dosage schedule to produce an overall reduction in the level of serum myostatin measured in the patient, and preferably to bring the myostatin level within the a range determined for normal, healthy individuals.

Antisense composition and method for treating muscle atrophy

Compositions and methods for treating hypertension in a subject are provided, including administering an antisense oligomer effective to reduce expression of cytochrome P450 3A5 (CYP3A5) enzyme. The antisense oligomer includes phosphorodiamidate morpholino oligonucleotide (PMO), phosphorothioate 2'-O-methyl oligoribonucleotides (PSO), locked nucleic acid nucleotide, locked nucleic acid analog nucleotide, or another modified oligonucleotide backbone or nuclease-resistant backbone. The antisense oligomer is administered transdermally, subcutaneously, or orally, and optionally with a pharmaceutically acceptable carrier. In one embodiment, the antisense oligomer is an oligomer that is antisense to mRNAs that encode CYP3A5, for instance targeted at the AUG start site of the mRNAs that encode CYP3A5 or at a G4 structure within CYP3A5.

Renal selective inhibition of cytochrome P450 3A5

Antisense compositions targeted against an mRNA sequence coding for a selected protein, at a region having its 5' end from 1 to about 25 base pairs downstream of a normal splice acceptor junction in the preprocessed mRNA, are disclosed. The antisense compound is RNase-inactive, and is preferably a phosphorodiamidate-linked morpholino oligonucleotide. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.

Splice-region antisense composition and method

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 for enhancing, by at least 10 fold, the antibacterial activity of an antisense oligonucleotide composed of morpholino subunits linked by phosphorus-containing intersubunit linkages. The method includes one or both of: conjugating an arginine-rich carrier to a 3' or 5&#x2032; end of the oligonucleotide and modifying the oligonucleotide to contain 20%-50% intersubunit linkages that are positively charged at physiological pH. Also disclosed is an antisense oligonucleotide having enhanced antibacterial activity by virtue of one or both modifications.

Antibacterial antisense oligonucleotide and method

Provided herein are antisense oligonucleotides, compositions comprising antisense oligonucleotides, and methods for the use of antisense oligonucleotides in manipulating translation. Expression of isoforms of proteins expressed from different start codons of the same transcript are inhibited by antisense oligonucleotides, which may also enhance expression of non-target isoforms.

Methods and compositions for manipulating translation of protein isoforms from alternative initiation of start sites

dsRNA molecules comprising oligonucleotide analogs having modified intersubunit linkages and/or terminal groups

A method and compound for treating skeletal muscle mass deficiency in a human subject are disclosed. The composition is an oligomer of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5' exocyclic carbon of an adjacent subunit, contains between 10-40 nucleotide bases, has a base sequence effective to hybridize to an expression-sensitive region of processed or preprocessed human myostatin RNA transcript, identified, in its processed form, by SEQ ID NO: 6, and is capable of uptake by target muscle cells in the subject. In practicing the method, the compound is administered in an amount and at a dosage schedule to produce an overall reduction in the level of serum myostatin measured in the patient, and preferably to bring the myostatin level within the a range determined for normal, healthy individuals.

The present invention provides antisense antiviral compounds, compositions, and methods of their use and production, mainly for inhibiting the replication of viruses of the Filoviridae family, including Ebola and Marburg viruses. The compounds, compositions, and methods also relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds include phosphorodiamidate morpholino oligonucleotides (PMOplus) having a nuclease resistant backbone, about 15-40 nucleotide bases, at least two but typically no more than half piperazine-containing intersubunit linkages, and a targeting sequence that is targeted against the AUG start site region of Ebola virus VP35, Ebola virus VP24, Marburg virus VP24, or Marburg virus NP, including combinations and mixtures thereof.

Antisense antiviral compounds and methods for treating a filovirus infection

A method and antisense compound for inhibiting the growth of pathogenic bacterial cells are disclosed. The compound contains no more than 12 nucleotide bases and has a targeting nucleic acid sequence of no fewer than 10 bases in length that is complementary to a target sequence containing or within 10 bases, in a downstream direction, of the translational start codon of a bacterial mRNA that encodes a bacterial protein essential for bacterial replication. The compound binds to a target mRNA with a Tof between 50&#xb0; to 60&#xb0; C. The relatively short antisense compounds are substantially more active than conventional antisense compounds having a targeting base sequence of 15 or more bases.

Antisense antibacterial method and compound

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Corvallis, OR, United States of America

Patrick L Iversen