# US 2010/0168215 A1 · Methods and compositions for the treatment of neurological disease

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- Number: US 2010/0168215 A1
- Document ID: US20100168215A1
- Status: Published application
- Kind: A1
- Application number: 12/714,613
- Filed: 2010-03-01
- Published: 2010-07-01
- Earliest claimed: 2004-10-14
- Assignees: Neurologix, Inc.
- Inventors: Matthew J. During; Annamaria Vezzani
- Web page: https://patentgrep.com/patent/US20100168215A1

## CPC

- C12N 15/86: Viral vectors
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/10: for petit-mal
- A61P 25/12: for grand-mal
- C07K 14/57545: {Neuropeptide Y}
- C12N 9/88: Lyases (4.)
- A01K 2207/05: Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose
- A01K 2207/20: Animals treated with compounds which are neither proteins nor nucleic acids
- A01K 2227/105: Murine
- A01K 2267/0356: Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14145: Special targeting system for viral vectors
- C12N 2810/6027: ssDNA viruses
- C12N 2830/008: cell type or tissue specific enhancer/promoter combination
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention relates to a method for delivering a nucleic acid sequence encoding neuropeptide Y, or a derivative or functional fragment thereof, to a mammalian nervous system target cell. The expression of exogenous NPY, or a derivative or a functional fragment thereof in the target cell(s) provides therapeutic benefit for subjects afflicted with a neurological disorder.

## Claims

### Claim 1

A method for delivering a nucleic acid sequence to a mammalian nervous system target cell, wherein said nucleic acid sequence is expressible in the target cell for greater than three months, said method comprising administering an expression vector to the target cell, wherein said expression vector comprises a nucleic acid sequence encoding neuropeptide Y, or a derivative or functional fragment thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the nucleic acid sequence encoding neuropeptide Y, or a derivative or functional fragment thereof, is expressed in said target cell either constitutively or under regulatable conditions.

### Claim 3 (depends on 2)

The method of claim 2, wherein expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell alters neuronal excitability.

### Claim 4 (depends on 2)

The method of claim 2, wherein expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell reduces neuronal excitability.

### Claim 5 (depends on 2)

The method of claim 2, wherein expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell reduces symptoms associated with neuronal hyperexcitability.

### Claim 6 (depends on 1)

The method of claim 1, wherein the expression vector is a viral or a non-viral expression vector.

### Claim 7 (depends on 6)

The method of claim 6, wherein the viral expression vector is an adeno-associated virus (AAV) vector, a lentivirus vector, an adenovirus vector, or a herpes simplex virus (HSV) vector.

### Claim 8 (depends on 7)

The method of claim 7, wherein the viral expression vector is an AAV vector capable of transducing the target cell and said AAV vector is free of both wildtype and helper virus.

### Claim 9 (depends on 8)

The method of claim 8, wherein the AAV vector is a serotype 2 AAV vector or a chimeric serotype 1/2 AAV vector.

### Claim 10 (depends on 2)

The method of claim 2, wherein the nucleic acid sequence encoding neuropeptide Y, or a derivative or functional fragment thereof, is operably linked to an inducible regulatory sequence, wherein activation of said inducible regulatory sequence effects transcription of messenger RNA encoding neuropeptide Y from said nucleic acid sequence.

### Claim 11 (depends on 10)

The method of claim 10, wherein said inducible regulatory sequence renders NPY expression nervous system-specific or central nervous system-specific.

### Claim 12 (depends on 10)

The method of claim 10, wherein expression of neuropeptide Y is specific to a medial temporal lobe or temporal cortex of the central nervous system.

### Claim 13 (depends on 12)

The method of claim 12, wherein expression of neuropeptide Y in the medial temporal lobe is localized to the hippocampus and/or amygdala.

### Claim 14 (depends on 12)

The method of claim 12, wherein the expression is neural or glial specific.

### Claim 15 (depends on 1)

The method of claim 1, wherein the target cell is a mammalian cell of a mammalian order selected from the group consisting of Primata, Rodenta, Carnivora and Arteriodactyla.

### Claim 16 (depends on 15)

The method of claim 15, wherein the target cell is a human cell.

### Claim 17 (depends on 1)

The method of claim 1, wherein the target cell is in cell culture.

### Claim 18 (depends on 1)

The method of claim 1, wherein the target cell is in a living mammal.

### Claim 19 (depends on 18)

The method of claim 18, wherein the vector is delivered to essentially all nervous system cells of the mammal.

### Claim 20 (depends on 18)

The method of claim 18, wherein the vector is specifically delivered to particular cell types or regions of the nervous system of the mammal.

### Claim 21 (depends on 1)

The method of claim 1, wherein said method for delivering nucleic acid encoding neuropeptide Y to cells of the nervous system to effect expression of neuropeptide Y in cells of the nervous system treats a disorder of the nervous system.

### Claim 22 (depends on 21)

The method of claim 21, wherein said disorder of the nervous system is epilepsy.

### Claim 23 (depends on 22)

The method of claim 22, wherein said epilepsy is intractable epilepsy.

### Claim 24 (depends on 23)

The method of claim 23, wherein said epilepsy is temporal lobe epilepsy.

### Claim 25 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or a derivative or functional fragment thereof.

### Claim 26 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or an amino acid sequence at least 90% homologous to SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8.

### Claim 27 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or an amino acid sequence at least 85% homologous to SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8.

### Claim 28 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a derivative or functional fragment thereof.

### Claim 29 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a nucleic acid sequence at least 90% homologous to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7.

### Claim 30 (depends on 1)

The method of claim 1, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a nucleic acid sequence at least 85% homologous to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7.

### Claim 31 (depends on 18)

The method of claim 18, wherein said administering is by stereotaxic microinjection.

### Claim 32

An AAV vector which retains only the replication and packaging signals of AAV, and which comprises a nucleic acid sequence encoding neuropeptide Y, or a derivative or a functional fragment thereof.

### Claim 33 (depends on 32)

The AAV vector of claim 32, wherein said nucleic acid sequence comprises a nucleic acid sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a derivative or a functional fragment thereof.

### Claim 34 (depends on 32)

The AAV vector of claim 32, wherein said nucleic acid sequence encodes an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or a derivative or a functional fragment thereof.

### Claim 35 (depends on 32)

A composition comprising an AAV vector of claim 32 and a pharmaceutically acceptable carrier.

### Claim 36 (depends on 33)

A composition comprising an AAV vector of claim 33 and a pharmaceutically acceptable carrier.

### Claim 37 (depends on 34)

A composition comprising an AAV vector of claim 34 and a pharmaceutically acceptable carrier.

### Claim 38

A method for treating a mammal with a neurological disease, said method comprising administering an expression vector to a target cell in the mammal, wherein said expression vector comprises a nucleic acid sequence encoding neuropeptide Y, or a derivative or functional fragment thereof, and wherein said administering results in expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell and said expression reduces the symptoms of the neurological disease, thereby treating the mammal with the neurological disease.

### Claim 39 (depends on 38)

The method of claim 38, wherein the expression vector is a viral or a non-viral expression vector.

### Claim 40 (depends on 39)

The method of claim 39, wherein the viral expression vector is an adeno-associated virus (AAV) vector, a lentivirus vector, an adenovirus vector, or a herpes simplex virus (HSV) vector.

### Claim 41 (depends on 38)

The method of claim 38, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or a derivative or a functional fragment thereof.

### Claim 42 (depends on 41)

The method of claim 41, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or an amino acid sequence at least 90% homologous to SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8.

### Claim 43 (depends on 41)

The method of claim 41, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence encoding an amino acid sequence comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8, or an amino acid sequence at least 85% homologous to SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8.

### Claim 44 (depends on 38)

The method of claim 38, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a derivative or a functional fragment thereof.

### Claim 45 (depends on 38)

The method of claim 38, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a nucleic acid sequence at least 90% homologous to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7.

### Claim 46 (depends on 38)

The method of claim 38, wherein said nucleic acid sequence encoding neuropeptide Y is a nucleic acid sequence comprising SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7, or a nucleic acid sequence at least 85% homologous to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, or SEQ ID NO: 7.

### Claim 47 (depends on 38)

The method of claim 38, wherein said neurological disease is epilepsy.

### Claim 48 (depends on 38)

The method of claim 38, wherein said neurological disease is intractable epilepsy.

### Claim 49 (depends on 38)

The method of claim 38, wherein said neurological disease is temporal lobe epilepsy.

### Claim 50 (depends on 38)

The method of claim 38, wherein said administering is by stereotaxic microinjection.

### Claim 51 (depends on 38)

The method of claim 38, wherein said administering is by stereotaxic microinjection to a medial temporal lobe or temporal cortex of the central nervous system.

### Claim 52 (depends on 51)

The method of claim 51, wherein said administering to the medial temporal lobe is localized to the hippocampus and/or amygdala.

### Claim 53 (depends on 32)

A method for delivering a nucleic acid sequence to a mammalian nervous system target cell, wherein said nucleic acid sequence is expressible in the target cell for greater than three months, said method comprising administering an adeno-associated virus (AAV) vector to the target cell, wherein said vector transduces the target cell; and wherein said AAV vector comprises an AAV vector of claim 32, and is free of both wildtype and helper virus.

### Claim 54 (depends on 35)

A method for delivering a nucleic acid sequence to a mammalian nervous system target cell, wherein said nucleic acid sequence is expressible in the target cell for greater than three months, said method comprising administering a composition of claim 35 to the target cell, said composition comprising an AAV vector capable of transducing the target cell; and wherein said AAV vector is free of both wildtype and helper virus.

### Claim 55 (depends on 32)

A method for treating a mammal with a neurological disease, said method comprising administering an adeno-associated virus (AAV) vector to a target cell in the mammal, wherein said AAV vector comprises an AAV vector of claim 32, and wherein said administering results in expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell and said expression reduces the symptoms of the neurological disease, thereby treating the mammal with the neurological disease.

### Claim 56 (depends on 35)

A method for treating a mammal with a neurological disease, said method comprising administering a composition of claim 35 to the target cell, said composition comprising an AAV vector capable of transducing the target cell and wherein said administering results in expression of neuropeptide Y, or a derivative or functional fragment thereof, in said target cell and said expression reduces the symptoms of the neurological disease, thereby treating the mammal with the neurological disease.