Isis Pharmaceuticals, Inc.

Pharmaessentia Corporation

Ching-Leou Teng

Muthiah Manoharan

Phillip Dan Cook

David J Ecker

Gregory E Hardee

Lloyd G Tillman

Bryan T H Wu

Tsai-Kuei Shen

Ming-Pin Hsu

Greg Hardee

The present invention relates to compositions and methods which enhance the local and systemic uptake and delivery of oligonucleotides and nucleic acids via non-parenteral routes of administration. Pharmaceutical compositions comprising oligonucleotides disclosed herein include, for systemic delivery, emulsion and microemulsion formulations for a variety of applications and oral dosage formulations. It has also surprisingly been discovered that oligonucleotides may be locally delivered to colonic sites by rectal enemas and suppositories in simple solutions, e.g., neat or in saline. Such pharmaceutical compositions of oligonucleotides may further include one or more penetration enhancers for the transport of oligonucleotides and other nucleic acids across mucosal membranes. The compositions and methods of the invention are utilized to effect the oral, buccal, rectal or vaginal administration of an antisense oligonucleotide to an animal in order to modulate the expression of a gene in the animal for investigative, therapeutic, palliative or prophylactic purposes.

Compositions and methods for non-parenteral delivery of oligonucleotides

A method of reducing formation of non-natural disulfide bonds in a mature IFN-&#x3b1; by adding one or more amino acid residues to its N-terminus cystein. Also disclosed herein is the IFN-&#x3b1; thus modified.

N-terminal modified interferon-alpha

The present invention relates to compositions and methods which enhance the transport of nucleic acids, especially oligonucleotides at various sites in the alimentary canal of an animal. The methods and compositions enhance the transport of oligonucleotides across the mucosa of the alimentary canal via the use of one or more penetration enhancers. The invention features the use of various fatty acids, bile salts, chelating agents and other penetration enhancers, as well as carrier compounds, to enhance the stability of nucleic acids and/or their transport across and/or into cells of the alimentary canal. In one preferred embodiment, the compositions and methods of the invention are utilized to effect the oral delivery of an antisense oligonucleotide to an animal in order to modulate the expression of a gene in the animal for investigative, therapeutic or prophylactic purposes.

Compositions and methods for the delivery of oligonucleotides via the alimentary canal

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San Diego, CA, United States of America

Ching-Leou Teng