Natural antisense and non-coding RNA transcripts as drug targets

• US 9,803,195 B2
• Filed: 07/31/2012
• Issued: 10/31/2017
• 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
• Primary Examiner(s): Angell, Jon E
• Application Number:
  US13/563,581
• Publication Number:
  US 20130053428A1
• Time in Patent Office: 1,918 Days
• 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 method of treating Alzheimer'"'"'s Disease comprising administering to a patient in need thereof at least one nucleic acid molecule comprising a sequence selected from:

SEQ ID NOS;

4, 5, 6, 7, 8, 40, 41, 42, 43, 44, 45, 58, 59, 60, 61, 64, 65, 66, and 67.

2. The method of claim 1, wherein the at least one nucleic acid molecule is administered in a pharmaceutically acceptable carrier.

3. The method of claim 1, 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.

4. The method of claim 3, wherein at least one of the at least two nucleic acid molecules comprises a sequence selected from:

SEQ ID NOS;

41, 42, 43, 44, and 45, and wherein the at least two nucleic acid molecules are present in a pharmaceutically acceptable carrier.

5. The method of claim 1, wherein varying combinations of at least two nucleic acid molecules, each comprising a sequence selected from:

SEQ ID NOS;

4, 5, 6, 7, 8, 40, 41, 42, 43, 44, 45, 58, 59, 60, 61, 64, 65, 66, and 67, are administered to the patient over a course of treatment.

12. The method of claim 5, wherein the at least two nucleic acid molecules are administered in a pharmaceutical carrier.

6. A method of treating a disease or condition in a subject in need of treatment thereof by modulating expression of a target gene, the method comprising:

targeting a nucleic acid molecule of 10 to 30 nucleotides in length to a natural anti-sense transcript of the target gene, wherein the target 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

, I530027A02, Kif20a, PINK-AS, aHIF1α

, Gnbp3g-AS, AdmR-AS, A230019L24, BACE or CtpW-AS, wherein the nucleic acid molecule targeting the natural anti-sense transcript is complementary to the natural antisense transcript; and

, binding of the nucleic acid molecule to the natural antisense transcript, whereby expression of the target gene is modulated.

7. The method of claim 6, wherein the nucleic acid molecules are RNA molecules.

8. The method of claim 6, wherein the nucleic acid molecules targeting the natural antisense transcripts bind said transcripts in convergent or divergent orientations with respect to each other, or are fully overlapping.

9. The method of claim 6, wherein the targeted natural antisense transcript is a coding or non-coding transcript.

10. The method of claim 6, wherein the targeted gene encodes PINK-AS, aHIF1α

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

11. The method of claim 9, wherein the targeted natural antisense transcript is from a target gene selected from:

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, and Kif20a.