# US 2008/0187492 A1 · Drosophila Models For Diseases Affecting Learning and Memory

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- Number: US 2008/0187492 A1
- Document ID: US20080187492A1
- Status: Published application
- Kind: A1
- Application number: 11/578,077
- Filed: 2005-04-14
- Published: 2008-08-07
- Earliest claimed: 2004-04-16
- Inventors: Sean M.J. McBride; Thomas A. Jongens; Catherine H. Choi
- Web page: https://patentgrep.com/patent/US20080187492A1

## CPC

- C07K 14/4702: {Regulators; Modulating activity}
- A01K 67/0275: Genetically modified vertebrates, e.g. transgenic
- A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure}
- 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
- C07K 14/4711: {Alzheimer's disease; Amyloid plaque core protein}
- C12N 15/8509: {for producing genetically modified animals, e.g. transgenic}
- A01K 2217/05: Animals comprising random inserted nucleic acids (transgenic)
- A01K 2227/706: Insects, e.g. Drosophila melanogaster, medfly
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Methods of evaluating a compound for the ability to reduce a mental defect in a metazoan are provided, where the mental defect is caused by Fragile X syndrome, a tauopathy, Huntington's disease, neurofibromatosis 1, Parkinson's disease. The methods comprise determining whether the compound reduces a mental effect of the analogous disease in a Drosophila melanogaster Also provided are methods of evaluating a compound for the ability to improve learning or memory in a mammal. The methods comprise determining whether the compound improves learning or memory in a Drosophila melanogaster that is deficient in a dFRM1. Additionally, methods of treatment of a mammal deficient in expression of an FMR1 gene are provided. The methods comprise treating the mammal with a compound in a pharmaceutically acceptable excipient, where the compound inhibits expression or activity of a group II or group I metabotropic glutamate receptor (mGluR), an inositol trisphosphate receptor (InsP3R), a glycogen synthase kinase-3β (GSK-3β), or a phosphodiesterase-4 (PDE-4) in the mammal.

## Claims

### Claim at position 1

1: A method of evaluating a compound for the ability to reduce a mental defect in a metazoan, where the mental defect is caused by a disease, wherein the disease is Fragile X syndrome, a tauopathy, Huntington's disease, neurofibromatosis 1, Parkinson's disease, or a disease analogous in the metazoan to Fragile X syndrome, a tauopathy, Huntington's disease, neurofibromatosis 1, or Parkinson's disease, the method comprising determining whether the compound reduces a mental effect of an analogous disease in a Drosophila.

### Claim at position 2 (depends on 1)

2: The method of claim 1, wherein the mental defect is in memory, orientation, learning, attention, reasoning, language, and/or the ability to perform simple tasks.

### Claim at position 3 (depends on 1)

3: The method of claim 1, wherein the disease is Fragile X syndrome and the analogous disease in a Drosophila is caused by a deficiency in a dFMR1 protein.

### Claim at position 4 (depends on 1)

4: The method of claim 1, wherein the disease is a tauopathy and the analogous disease in a Drosophila is caused by expression of a human tau protein.

### Claim at position 5

5-6. (canceled)

### Claim at position 6 (depends on 1)

7: The method of claim 1, wherein the disease is Alzheimer's and the analogous disease in a Drosophila is caused by expression of a mutant presenilin gene associated with Alzheimer's.

### Claim at position 7

8-11. (canceled)

### Claim at position 8 (depends on 1)

12: The method of claim 1, wherein the compound is an inhibitor of a glutamate receptor (GluR).

### Claim at position 9

13-34. (canceled)

### Claim at position 10

35: A method of improving learning or memory in a mammal, the method comprising treating the mammal with a compound in an amount sufficient to improve learning or memory in the mammal, wherein the compound inhibits expression or activity of a group II or group III metabotropic glutamate receptor (mGluR), an inositol trisphosphate receptor (InsP3R), a glycogen synthase kinase-3β (GSK-3β), or a phosphodiesterase-4 (PDE-4) in the mammal.

### Claim at position 11 (depends on 35)

36: The method of claim 35, wherein the mammal has Fragile X syndrome, a tauopathy, Huntington's disease, neurofibromatosis 1, Parkinson's disease, or a non-human disease analogous to Fragile X syndrome, a tauopathy, Huntington's disease, neurofibromatosis 1, or Parkinson's disease.

### Claim at position 12 (depends on 35)

37: The method of claim 35, wherein the mammal is treated with LiCl.

### Claim at position 13 (depends on 35)

38: The method of claim 35, wherein the mammal is treated with an inhibitor of a group II mGluR where the inhibitor is at a concentration that it is specific for a group II mGluR.

### Claim at position 14 (depends on 35)

39: The method of claim 35, wherein the mammal is treated with an inhibitor of a group III mGluR where the inhibitor is at a concentration that is specific for a group III mGluR.

### Claim at position 15 (depends on 35)

40: The method of claim 35, wherein the compound is 2-methyl-6-(phenylethynyl)pyridine (MPEP), 2-amino-4-phosphonobutanoic acid (AP-4), (RS)-α-methylserine-O-phosphate monophenyl ester, (RS)-1-amino-5-phosphonoindan-1-carboxylic acid [(RS)-APICA], (RS)-α-methyl-4-tetrazolylphenylglycine (MTPG), (2S)-α-ethylglutamic acid (EGLU), (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propionic acid (LY341495), TDZD-8,1-azakenpaullone, MAP4, or 4-[3-(Cyclopentyl)-4-methoxyphenyl]-2-pyrrolidinone (rolipram).

### Claim at position 16 (depends on 35)

41: The method of claim 35, wherein the compound comprises a nucleic acid.

### Claim at position 17

42-44. (canceled)

### Claim at position 18

45: A method of treating a mammal having Fragile X disease or a non-human disease analogous to Fragile X disease, the method comprising treating the mammal with a compound that inhibits expression or activity of a group II or group III metabotropic glutamate receptor (mGluR), an inositol trisphosphate receptor (InsP3R), a glycogen synthase kinase-3β (GSK-3β), or a phosphodiesterase-4 (PDE-4) in the mammal.

### Claim at position 19 (depends on 45)

46: The method of claim 45, wherein the mammal exhibits a deficiency in memory, orientation, learning, attention, reasoning, language and/or the ability to perform simple tasks.

### Claim at position 20 (depends on 45)

47: The method of claim 45, wherein the mammal is treated with LiCl.

### Claim at position 21 (depends on 45)

48: The method of claim 45, wherein the mammal is treated with an inhibitor of a group II mGluR where the inhibitor is at a concentration that it is specific for a group II mGluR.

### Claim at position 22 (depends on 45)

49: The method of claim 45, wherein the mammal is treated with an inhibitor of a group III mGluR where the inhibitor is at a concentration that is specific for a group III mGluR.

### Claim at position 23 (depends on 45)

50: The method of claim 45, wherein the compound is 2-methyl-6-(phenylethynyl)pyridine (MPEP), 2-amino-4-phosphonobutanoic acid (AP-4), (RS)-α-methylserine-O-phosphate monophenyl ester, (RS)-1-amino-5-phosphonoindan-1-carboxylic acid [(RS)-APICA], (RS)-α-methyl-4-tetrazolylphenylglycine (MTPG), (2S)-α-ethylglutamic acid (EGLU), (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propionic acid (LY341495), TDZD-8,1-azakenpaullone, MAP4, or 4-[3-(Cyclopentyl)-4-methoxyphenyl]-2-pyrrolidinone (rolipram).

### Claim at position 24 (depends on 45)

51: The method of claim 45, wherein the compound comprises a nucleic acid.

### Claim at position 25

52-88. (canceled)