Abstract: The present invention provides an improved method for reducing the risk or severity of restenosis following cardiac angioplasty. The method includes administering to a target vessel region, a morpholino antisense compound having a phosphorus-containing backbone linkages, and spanning the start codon of a human c-myc mRNA. Also disclosed are novel antisense compounds and compositions, and a method for assaying the effectiveness of antisense delivery and uptake to a target vessel region.

Abstract: 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.

Abstract: 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 of Enterovirus and/or Rhinovirus infection 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.

Abstract: 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.

Abstract: A method and compound for suppressing an immune response in a mammalian subject, for the treatment or prevention of an autoimmune condition or transplantation rejection are disclosed. The compound is an antisense oligonucleotide analog compound having a targeting sequence complementary to a preprocessed CTLA-4 mRNA region identified by SEQ ID NO: 1, spanning the splice junction between intron 1 and exon 2 of the preprocessed mRNA of the subject. The compound is effective, when administered to a subject, to form within host cells, a heteroduplex structure (i) composed of the preprocessed CTLA-4 mRNA and the oligonucleotide compound, (ii) characterized by a Tm of dissociation of at least 45° C., and (iii) resulting in an increased ratio of processed mRNA encoding ligand-independent CTLA-4 to processed mRNA encoding full-length CTLA-4.

Abstract: 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 of Enterovirus and/or Rhinovirus infection 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.

Abstract: 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 Tm of between 50° to 60° C. The relatively short antisense compounds are substantially more active than conventional antisense compounds having a targeting base sequence of 15 or more bases.

Abstract: The invention provides antisense antiviral compounds and methods of their use in inhibition of growth of human immunodeficiency virus-1 (HOV-1), as in treatment of a viral infection. The antisense antiviral compounds have morpholino subunits linked by uncharged phosphorodiamidate linkages interspersed with cationic phosphorodiamidate linkages. An exemplary embodiment of the invention provides an antisense compound directed to the HIV Vif gene, causing the production of defective HIV- 1 virions in an infected individual.

Abstract: 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? subgenomic region. In practicing the method, infected cells are exposed to the compound in an amount effective to inhibit viral replication.

Abstract: 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, including partially positively charged, 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? 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? terminus of the positive sense cRNA and; and c) the 50 bases surrounding the AUG start codon of an influenza viral mRNA.

Abstract: An antiviral antisense composition and method for treating foot-and-mouth disease virus (FMDV) in veterinary animals is disclosed. The composition contains an antisense compound that has a sequence effective to target at least 12 contiguous bases of an FMDV RNA sequence within a region of the positive-strand genomic RNA defined by SEQ ID NO: 25, and preferably, one of the viral sequences within SEQ ID NO:25 identified by SEQ ID NOS: 26-28. The composition is administered in a therapeutically effective amount in treating FMDV.

Abstract: 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 a phosphorodiamidate-linked morpholino oligonucleotide containing uncharged phosphorodiamidate linkages interspersed with cationic phosphorodiamidate linkages. Such targeting is effective to inhibit natural mRNA splice processing, produce splice variant mRNAs, and inhibit normal expression of the protein.

Abstract: 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 AUG start site region of VP35, as exemplified by SEQ ID NOS:67-71 or ii) the AUG start site region of VP24, as exemplified by SEQ ID NOS:72-76.

Abstract: A method and composition for inducing human dendritic cells to a condition of reduced capacity for antigen-specific activation of T cells, and, in mature dendritic cells, increased production of extracellular IL-10 is disclosed. A population of dendritic cells is exposed to a substantially uncharged antisense compound, including partially positively charged, containing 12-40 subunits and a base sequence effective to hybridize to an expression-sensitive region of a preprocessed or processed human CD86 transcript identified, in its processed form, by SEQ ID NO:33, to form a duplex structure between said compound and transcript having a Tm of at least 45° C. Formation of the duplex blocks expression of full-length CD86 in said cells, which in turn leads to reduced capacity for antigen-specific activation of T cells, and, in mature dendritic cells, increased production of extracellular IL-10.

Abstract: The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Flaviviridae, Picomoviridae, 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 1240 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.

Abstract: The present invention provides an improved method for reducing the risk or severity of restenosis following cardiac angioplasty. The method includes administering to a target vessel region, a morpholino antisense compound having uncharged phosphorus-containing backbone linkages, and spanning the start codon of a human c-myc mRNA. Also disclosed are novel antisense compounds and compositions, and a method for assaying the effectiveness of antisense delivery and uptake to a target vessel region.

Abstract: A therapeutic oligomer-peptide conjugate, and methods of using the conjugate are disclosed. The conjugate includes (a) a substantially uncharged oligonucleotide analog compound having a base sequence that includes a string of bases that are complementary to four or more contiguous cytosine bases in a target nucleic acid region to which the compound is intended to bind, and (b) conjugated to the compound, an arginine-rich peptide effective to enhance the uptake of the compound into target cells. The string of bases in the compound includes at least one inosine base positioned in the string so as to limit the number of contiguous guanine bases in said string to three or fewer. The conjugate has greater cellular uptake than the compound alone, by virtue of the arginine-rich peptide, and substantially greater antisense activity greater activity than the conjugate in the absence of inosine-for guanine substitutions.

Abstract: A composition of polymer molecules effective to bind, with substantially uniform binding affinity, to a single-stranded polynucleotide containing a target sequence of bases. The polymer molecules are composed of a sequence of base-pairing moieties effective to hydrogen bond to corresponding, complementary bases in the target sequence, under selected binding conditions, and a predominantly uncharged, achiral backbone supporting the base-pairing moieties at positions and in orientations which allow hydrogen bonding between the pairing moieties of the polymer and the corresponding complementary bases in the target sequence. The composition has diagnostic uses, in a solid-support assay system, and therapeutic uses involving inhibition or inactivation of target polynucleotides.

Abstract: A diagnostic reagent and system for determination of a single-stranded polynucleotide analyte having a selected target sequence. The reagent includes a solid support and multiple support-bound polymers designed to bind specifically to the analyte. Each polymer is composed of a sequence of base-complementary recognition moieties which can bind specifically to corresponding contiguous bases in the analyte target sequence, and an unbranched, substantially uncharged, substantially stereoregular backbone. A reporter in the system contains (a) a polycationic tail effective to bind electrostatically to the analyte, under conditions in which the reporter does not bind to the substantially uncharged polymers, and (b) reporter groups by which the presence of the reporter can be detected.

Abstract: A composition of polymer molecules effective to bind, with substantially uniform binding affinity, to a single-stranded polynucleotide containing a target sequence of bases. The polymer molecules are composed of a sequence of base-pairing moieties effective to hydrogen bond to corresponding, complementary bases in the target sequence, under selected binding conditions, and a predominantly uncharged, achiral backbone supporting the base-pairing moieties at positions and in orientations which allow hydrogen bonding between the pairing moieties of the polymer and the corresponding complementary bases in the target sequence. The composition has diagnostic uses, in a solid-support assay system, and therapeutic uses involving inhibition or inactivation of target polynucleotides.