Antisense composition and method for treating cancer

• US 7,402,574 B2
• Filed: 03/10/2005
• Issued: 07/22/2008
• Est. Priority Date: 03/12/2004
• Status: Expired due to Fees

• Current Assignee: Avi Biopharma, Inc.
• Original Assignee: Avi Biopharma, Inc.
• Inventors: Iversen, Patrick L., Bestwick, Richard K., Roy, Hemant K.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US11/077,871
• Publication Number:
  US 20050261249A1
• Time in Patent Office: 1,230 Days
• Field of Search: None
• US Class Current: 514/44.00A
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61P 35/00 Antineoplastic 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 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/3145 with the nitrogen in 3' or 5'-position
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring

Abstract

A method and composition for treating colorectal cancer is disclosed. The method involves administering to a subject, a therapeutically effective amount of a morpholino antisense compound (i) having a nuclease-resistant backbone, (ii) capable of uptake by target cancer cells in the subject, (iii) containing between 10-40 nucleotide bases, and (iv) having a base sequence effective to hybridize to a region of processed or preprocessed human SNAIL RNA transcript.

Claims

1. A method of treating colorectal cancer in a subject, comprising:

administering to a subject a therapeutically effective amount of a composition of a morpholino antisense oligonucleotide, wherein the oligonucleotide is of about 10-40 bases in length, comprises a nuclease-resistant backbone and a targeting sequence which forms a heteroduplex with a target region of processed or preprocessed human SNAIL RNA transcript affecting expression of SNAIL protein, and inhibits expression of active SNAIL protein in target cancer cells.

2. The method of claim 1, wherein the preprocessed SNAIL RNA transcript has the sequence of SEQ ID NO:

21.

3. The method of claim 1, wherein the heteroduplex has a Tm of dissociation of at least 45°

C.

4. The method of any one of claims 1, 2 or 3, wherein the oligonucleotide is composed of morpholino subunits and phosphorus-containing intersubunit linkages joining a morpholino nitrogen of one subunit to a 5′

exocyclic carbon of an adjacent subunit.

5. The method of claim 4, wherein the intersubunit linkages are uncharged.

6. The method of claim 4, wherein the morpholino subunits are joined by intersubunit linkages, in accordance with the structure:

7. The method of claim 1, wherein the administered composition is a conjugate of the oligonucleotide and an arginine-rich polypeptide effective to promote uptake of the oligonucleotide into target cells.

8. The method of claim 7, wherein the arginine-rich peptide is covalently coupled at its C terminus to the 3′

end of the antisense compound.

9. The method of claim 1, wherein the antisense oligonucleotide target region is a translation start site of the processed SNAIL transcript.

10. The method of claim 1, wherein the antisense oligonucleotide target region is a splice site of the preprocessed human SNAIL transcript.

11. The method of claim 1, wherein the antisense oligonucleotide is effective to inhibit cancer cell growth.

12. The method of claim 1, which further includes administering an additional chemotherapeutic agent to the subject.