Methods Relating to Peripheral Administration of Nogo Receptor Polypeptides

• US 20120219567A1
• Filed: 02/21/2012
• Published: 08/30/2012
• Est. Priority Date: 08/31/2006
• Status: Abandoned Application

• Current Assignee: Biogen Idec MA Inc. (Biogen, Inc.), Yale University
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.), Yale University
• Inventors: Strittmatter, Stephen M., Lee, Daniel H.S.
• Application Number:
  US13/401,590
• Publication Number:
  US 20120219567A1
• Time in Patent Office: Days
• US Class Current: 424/172.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/1703 from vertebrates
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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 25/08 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 25/22 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 27/02 Ophthalmic agents
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 14/4711 : Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 14/705 : Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/70571 : for neuromediators, e.g. serotonin receptor, dopamine receptor

Abstract

This invention relates to methods of treating diseases involving accumulation of Aβ plaques, including Alzheimer'"'"'s Disease by the peripheral administration of soluble Nogo receptor polypeptides. The invention also provides methods of increasing the plasma to brain ratio of Aβ peptide and enhancing Aβ peptide clearance via peripheral administration of soluble Nogo receptor polypeptides. This invention also provides methods of improving memory function or inhibiting memory loss via the peripheral administration of soluble Nogo receptor polypeptides. The invention also provides methods of decreasing the size and number of Aβ plaques in a mammal via peripheral administration of soluble Nogo receptor polypeptides.

Claims

1. A method of increasing the plasma to brain ratio of Aβ

peptide in a mammal or enhancing Aβ

clearance from the brain of a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a soluble Nogo receptor polypeptide, wherein said administration is peripheral to the central nervous system.

12. The method of claim 1, wherein said mammal is a human.

13. The method of claim 1, wherein said soluble Nogo receptor polypeptide is administered subcutaneously, parenterally, intravenously, intramuscularly, intraperitoneally, transdermally, inhalationaly or buccally.

14. The method of claim 1, wherein said soluble NgR1 polypeptide is 90% identical to a reference amino acid sequence is selected from the group consisting of:

(i) amino acids 27 to 310 of SEQ ID NO;

2;

(ii) amino acids 27 to 344 of SEQ ID NO;

2;

(iii) amino acids 27 to 445 of SEQ ID NO;

2;

(iv) amino acids 27 to 309 of SEQ ID NO;

2;

(v) amino acids 1 to 310 of SEQ ID NO;

2;

(vi) amino acids 1 to 344 of SEQ ID NO;

2;

(vii) amino acids 1 to 445 of SEQ ID NO;

2;

(viii) amino acids 1 to 309 of SEQ ID NO;

2;

(ix) variants or derivatives of any of said reference amino acid sequences, and

(x) a combination of one or more of said reference amino acid sequences or variants or derivatives thereof.

15. The method of claim 14, wherein said soluble NgR1 polypeptide is selected from the group consisting of:

(i) amino acids 27 to 310 of SEQ ID NO;

2;

(ii) amino acids 27 to 344 of SEQ ID NO;

2;

(iii) amino acids 27 to 445 of SEQ ID NO;

2;

(iv) amino acids 27 to 309 of SEQ ID NO;

2;

(v) amino acids 1 to 310 of SEQ ID NO;

2;

(vi) amino acids 1 to 344 of SEQ ID NO;

2;

(vii) amino acids 1 to 445 of SEQ ID NO;

2;

(viii) amino acids 1 to 309 of SEQ ID NO;

2;

(ix) variants or derivatives of any of said polypeptides; and

(x) a combination of one or more of said polypeptides or variants or derivatives thereof.

24. The method of claim 1, wherein said soluble Nogo receptor polypeptide comprises a first polypeptide fragment and a second polypeptide fragment, wherein said first polypeptide fragment comprises an amino acid sequence identical to a first reference amino acid sequence, except for up to twenty individual amino acid substitutions, wherein said first reference amino acid sequence is selected from the group consisting of:

(a) amino acids a to 445 of SEQ ID NO;

2,

(b) amino acids 27 to b of SEQ ID NO;

2, and

(c) amino acids a to b of SEQ ID NO;

2,

wherein a is any integer from 25 to 35, and b is any integer from 300 to 450; and

wherein said second polypeptide fragment comprises an amino acid sequence identical to a second reference amino acid sequence, except for up to twenty individual amino acid substitutions, wherein said second reference amino acid sequence is selected from the group consisting of;

(a) amino acids c to 445 of SEQ ID NO;

2,

(b) amino acids 27 to d of SEQ ID NO;

2, and

(c) amino acids c to d of SEQ ID NO;

2,

wherein c is any integer from 25 to 35, and d is any integer from 300 to 450.

28. The method of claim 14, wherein at least one amino acid residue of said, soluble NgR1 polypeptide is substituted with a different amino acid.

31. The method of claim 14, wherein said soluble NgR1 polypeptide is a cyclic polypeptide.

37. The method of claim 14, wherein said soluble NgR1 polypeptide further comprises a non-NgR1 moiety.

38. The method of claim 37, wherein said non-NgR1 moiety is a heterologous polypeptide fused to said soluble NgR1 polypeptide.

45. The method of claim 37, wherein said soluble NgR1 polypeptide is conjugated to a polymer.

51. The method of claim 1, wherein the therapeutically effective amount is from 0.001 mg/kg to 10 mg/kg of soluble Nogo receptor polypeptide.

54. The method of claim 1, wherein the soluble Nogo receptor polypeptide does not cross the blood-brain barrier.

55. The method of claim 1, wherein said soluble Nogo receptor polypeptide is coadministered with one or more anti-Aβ

antibodies.

56. The method of claim 55, wherein said soluble Nogo receptor polypeptide is coadministered with one or more additional therapeutic agents, selected from the group consisting of an adrenergic agent, anti-adrenergic agent, anti-androgen agent, anti-anginal agent, anti-anxiety agent, anticonvulsant agent, antidepressant agent, anti-epileptic agent, antihyperlipidemic agent, antihyperlipoproteinemic agent, antihypertensive agent, anti-inflammatory agent, antiobessional agent, antiparkinsonian agent, antipsychotic agent, adrenocortical steroid;

adrenocortical suppressant;

aldosterone antagonist;

amino acid;

anabolic steroid;

analeptic agent; and

rogen;

blood glucose regulator;

cardioprotectant agent;

cardiovascular agent;

cholinergic agonist or antagonist;

cholinesterase deactivator or inhibitor, cognition adjuvant or enhancer;

dopaminergic agent;

enzyme inhibitor, estrogen, free oxygen radical scavenger;

GABA agonist;

glutamate antagonist;

hormone;

hypocholesterolemic agent;

hypolipidemic agent;

hypotensive agent;

immunizing agent;

immunostimulant agent;

monoamine oxidase inhibitor, neuroprotective agent;

NMDA antagonist;

AMPA antagonist, competitive or-non-competitive NMDA antagonist;

opioid antagonist;

potassium channel opener;

non-hormonal sterol derivative;

post-stroke and post-head trauma treatment;

prostaglandin agent;

psychotropic agent;

relaxant agent;

sedative agent;

sedative-hypnotic agent;

selective adenosine antagonist;

serotonin antagonist;

serotonin inhibitor;

selective serotonin uptake inhibitor;

serotonin receptor antagonist;

sodium and calcium channel blocker;

steroid;

stimulant; and

thyroid hormone and inhibitor agents.

2. (canceled)

3. (canceled)

4. A method of reducing the number of Aβ

plaques or the size of Aβ

plaques in the brain of a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a soluble Nogo receptor polypeptide, wherein said administration is peripheral to the central nervous system.

5. (canceled)

6. A method of treating a disease associated with Aβ

plaque accumulation in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a soluble Nogo receptor polypeptide, wherein said administration is peripheral to the central nervous system.

7. The method of claim 6, wherein said disease is selected from the group consisting of Alzheimer'"'"'s disease, mild cognitive impairment, mild-to-moderate cognitive impairment, vascular dementia, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, senile dementia, Down'"'"'s syndrome, inclusion body myositis, age-related macular degeneration, primary amyloidosis, secondary amyloidosis and a condition associated with Alzheimer'"'"'s disease.

8. The method of claim 7, wherein said condition associated with Alzheimer'"'"'s disease is selected from the group consisting of hypothyroidism, cerebrovascular disease, cardiovascular disease, memory loss, anxiety, a behavioral dysfunction, a neurological condition, and a psychological condition.

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