NATURAL ANTISENSE AND NON-CODING RNA TRANSCRIPTS AS DRUG TARGETS

• US 20130053428A1
• Filed: 07/31/2012
• Published: 02/28/2013
• Est. Priority Date: 12/28/2005
• Status: Active Grant

• Current Assignee: University of Florida Research Foundation, Incorporated (State University System of Florida)
• Original Assignee: The Scripps Research Institute
• Inventors: WAHLESTEDT, Claes
• Granted Patent: US 9,803,195 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 2310/111 : spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2330/10 : naturally occurring

Abstract

Small interfering RNA (siRNA) knock down antisense transcripts, and regulate the expression of their sense partners. This regulation can either be discordant (antisense knockdown results in sense transcript elevation) or concordant (antisense knockdown results in concomitant sense transcript reduction).

Claims

1. A pharmaceutical composition for treating neurological disorders, comprising at least one nucleic acid molecule and variants thereof selected from the group consisting of:

SEQ ID NOS;

4-8, 40-61 and 64-67, in a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein the at least one nucleic acid molecule comprises at least two siRNA molecules targeting overlapping regions of a sense/antisense locus.

3. The pharmaceutical composition of claim 2, wherein the at least two siRNA molecules comprise at least one sequence selected from:

SEQ ID NOS;

4-8, and variants thereof.

4. The pharmaceutical composition of claim 2, wherein the at least two siRNA molecules comprise at least one sequence selected from:

SEQ ID NOS;

40-61, 64-67, and variants thereof.

5. The pharmaceutical composition of claim 2, wherein the at least two siRNA molecules comprise at least one sequence selected from:

SEQ ID NOS;

41-43 and SEQ ID NOS;

44-45, and variants thereof.

6. The pharmaceutical composition of claim 5, wherein the at least one nucleic acid molecule targets BACE transcripts.

7. An isolated nucleic acid comprising at least one sequence selected from:

SEQ ID NOS;

4-8, 40-61, 64-67, and variants thereof.

8. An expression vector comprising at least one sequence selected from:

SEQ ID NOS;

4-8, 40-61, 64-67, and variants thereof.

9. An isolated peptide encoded by any one or more of:

SEQ ID NOS;

4-8, 40-61, 64-67, and variants thereof.

10. An isolated antibody specific for any one or more of:

BACE-1 mRNA, BACE-1-AS RNA, SEQ ID NOS;

1-67, and peptides thereof.

11. A method of treating a neurological disorder comprising administering to a patient in need thereof at least one nucleic acid molecule comprising a sequence selected from:

SEQ ID NOS;

4-8, 40-61, 64-67, and variants thereof.

12. The method of claim 11, wherein the at least one nucleic acid molecule is administered in a pharmaceutically acceptable carrier.

13. The method of claim 11, comprising administering to the patient at least two nucleic acid molecules, wherein the at least two nucleic acid molecules are administered in combinations targeting overlapping regions of a sense/antisense locus.

14. The method of claim 13, wherein a pharmaceutical composition comprises a nucleic acid molecule comprising any sequence of:

SEQ ID NOS;

41-43, SEQ ID NOS;

44-45 and variants thereof.

15. The method of claim 11, wherein varying combinations of at least two of SEQ ID NOS:

4-8, 40-61, 64-67 and variants thereof are administered to the patient over a course of treatment.

16. The method of claim 11, wherein the neurological disorder comprises Alzheimer'"'"'s Disease, Aphasia, Bell'"'"'s Palsy, Creutzfeldt-Jakob Disease, Epilepsy, Encephalitis, Huntington'"'"'s Disease, a Neuromuscular Disorder, a Neuro-oncology Disorder, a Neuro-immunology Disorder, a Neuro-otology disorder, Pain, Phobia, a Sleep Disorder, Tourette'"'"'s Syndrome, Parkinson'"'"'s Disease, or a movement disorder.

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. A method of inhibiting gene expression comprising:

targeting a nucleic acid molecule to an anti-sense transcript and sense strand transcript, wherein the nucleic acid molecule targeting the anti-sense transcript is complementary to the anti-sense strand and the nucleic acid molecule targeting the sense transcript is complementary to the sense strand; and

,

binding of the nucleic acid to the anti-sense and sense transcript;

wherein, gene expression is inhibited.

22. The method of claim 21, wherein the nucleic acid molecules are RNA molecules.

23. The method of claim 21, wherein the nucleic acid molecules targeting the anti-sense and sense transcripts bind said transcripts in convergent or;

divergent orientations with respect to each other, or are overlapping.

24. The method of claim 21, wherein the targeted antisense or sense strand transcript is a coding or non-coding transcript.

25. The method of claim 21, wherein the inhibited gene encodes CD97, TS-α

, C/EBP delta, CDC23, PINK1, HIF1α

, Gnbp3g, Adrenomedullin AM1 receptor, 6330439J10 (3-oxoacid CoA transferase), CtpW85 (Cathepsin W), Ddx-39, rTS-α

, 1530027A02, Kif20a, PINK-AS, aHIF1α

, Gnbp3g-AS, AdmR-AS, A230019L24, BACE or CtpW-AS.

26. The method of claim 24, wherein the targeted coding transcript comprises a nucleic acid sequence encoding PINK-AS, aHIF1α

, Gnbp3g-AS, AdmR-AS, A230019L24, or CtpW-AS.

27. The method of claim 24, wherein the targeted non-coding nucleic acid comprises a nucleic acid sequence encoding CD97, TS-α

, C/EBP delta, CDC23, PINK1, HIF1α

, Gnbp3g, Adrenomedullin AM1 receptor, 6330439J10 (3-oxoacid CoA transferase), CtpW85 (Cathepsin W), Ddx-39, rTS-α

, 1530027A02, or Kif20a.

28. A pharmaceutical composition comprising at least one of SEQ ID NOs:

1-67 and variants thereof.

29. The pharmaceutical composition of claim 28, wherein the composition is used to treat age related macular degeneration.

30. An isolated nucleic acid molecule comprising at least one of SEQ ID NOs:

1-67 and variants thereof.

31. The isolated nucleic acid molecule of claim 30, comprising at least one modified nucleobase.

32. A composition comprising at least one nucleic acid sequences targeting at least one gene, wherein the at least one gene encodes CD97, TS-α

, C/EBP delta, CDC23, PINK1, HIF1α

, Gnbp3g, Adrenomedullin AM1 receptor, 6330439J10 (3-oxoacid CoA transferase), CtpW85 (Cathepsin W), Ddx-39, rTS-α

, 1530027A02, Kif20a, PINK-AS, aHIF1α

, Gnbp3g-AS, AdmR-AS, A230019L24, BACE or CtpW-AS.

33. A method of treating Parkinson'"'"'s Disease comprising administering to a patient in need thereof at least one nucleic acid molecule comprising a sequence selected from:

SEQ ID NOS;

1-3, and variants thereof.

34. The method of claim 33, wherein the at least one nucleic acid molecule is administered in a pharmaceutical carrier.