Method of down-regulating gene expression

• US 6,608,035 B1
• Filed: 06/06/2000
• Issued: 08/19/2003
• Est. Priority Date: 10/25/1994
• Status: Expired due to Fees

• Current Assignee: Idera Pharmaceuticals, Inc. (Aceragen Incorporated)
• Original Assignee: Hybridon, Inc. (Aceragen Incorporated)
• Inventors: Zhang, Ruiwen, Diasio, Robert B., Agrawal, Sudhir
• Primary Examiner(s): Shukla, Ram R.
• Assistant Examiner(s): ZARA, JANE J
• Application Number:
  US09/587,934
• Time in Patent Office: 1,169 Days
• Field of Search: 435/6, 435/91.1, 435/91.5, 435/455, 435/375, 935/34, 514/44, 536/23.1, 536/24.5, 536/25.3
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 31/7125 Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/312 Phosphonates
• CPC Class Codes: C12N 2310/3125 Methylphosphonates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed is a method of down-regulating the expression of a gene in an animal, wherein a pharmacological formulation comprising a chimeric oligonucleotide complementary to the gene is orally administered to an animal. The oligonucleotide administered has at least one phosphorothioate internucleotide linkage and at least one alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, phosphoramidite, phosphate ester, carbamate, carbonate, phosphate triester, acetamidate, or carboxymethyl ester internucleotide linkage.

Claims

1. A method for introducing an intact oligonucleotide into a mammal, comprising the step of orally administering an oligonucleotide of about 15 to 30 nucleotides, the oligonucleotide comprising phosphorothioate internucleoside linkages between adjacent nucleosides and further comprising at least one 2′

-O-alkoxyalkyl-ribonucleotide at each end, whereby the oligonucleotide is present in intact form in liver and kidney tissue of the mammal following oral administration.

2. The method of claim 1, wherein the 2′

-O-alkoxyalkyl ribonucleotide is a 2′

-O-methoxyethyl-ribonucleotide.