TREATMENT OF NEUROLOGICAL DISORDERS BY DSRNA ADMINISTRATION

• US 20080153768A1
• Filed: 07/17/2007
• Published: 06/26/2008
• Est. Priority Date: 09/04/2002
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Dorn, Gabriele, Hemmings, Maria Wanda, Hall, Jonathan, Wishart, William Leonard, Ganju, Pamposh
• Granted Patent: US 8,129,354 B2
• Time in Patent Office: Days
• US Class Current: 514/44
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/24 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 : 5-Methylcytosine
• CPC Class Codes: C12N 2310/335 : Modified T or U
• CPC Class Codes: C12N 2310/3525 : MOE, methoxyethoxy

Abstract

The present invention relates to methods to treat neurological disorders comprising intrathecal injection of an effective amount of a double-stranded (ds) RNA into a subject in need, wherein the dsRNA inhibits the expression of a target gene and to pharmaceutical compositions useful for such treatment.

Claims

1. A method to treat or ameliorate pain comprising intrathecal injection of an effective amount of a double-stranded (ds) RNA into a subject in need, wherein said dsRNA inhibits the expression of a target gene.

3. A method according to claim 1 wherein said pain is chronic neuropathic pain.

4. A method according to claim 3 wherein said chronic pain is selected from the group consisting of cancer pain, osteoarthritis pain, allodynia and hyperalgesia.

5. A method according to the preceding claim wherein said target gene is selected from among purine receptors P1 or P2.

6. The method according to the preceding claim wherein said target gene is P₂X₃ or P₂X₂.

7. A method as in the preceding claims wherein the subject in need is a human.

8. A method as in claim 1 wherein the subject in need is a rat.

9. A method according to claim 1 wherein at least 200 μ

g of dsRNA are intrathecally injected.

10. A method according to claim 1 wherein the dsRNA comprises a double-stranded region of 15 to 25 nt.

11. A method according to the preceding claims wherein the dsRNA comprises a 3′

overhang on the antisense or the sense strand, or both strands, of at least one nucleotide.

12. A method according to claim 11 wherein the overhang contains at least one modified nucleotide.

13. A method according to claim 11 wherein the overhang comprises at least one 2′

-MOE modified nucleotide.

14. A method according to claim 11 wherein the overhang comprises 4 Uracils.

15. A method according to claim 1 wherein the dsRNA comprises at least one phosphorothioate linkage.

2. (canceled)

16. A pharmaceutical composition comprising an effective amount of a double stranded RNA inhibiting the expression of P₂X₃ or P₂X₂ in an amount effective to treat chronic pain in a subject in need.

17. A pharmaceutical composition comprising an effective amount of at least one double stranded RNA, said double stranded RNA comprising a strand of the sequence selected from the group consisting of SEQ ID Nos:

7-10 and 13-18.

18. (canceled)

19. (canceled)

20. (canceled)