# US 9,012,224 B2 · Chimeric vectors

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- Number: US 9,012,224 B2
- Document ID: US9012224B2
- Status: Granted
- Kind: B2
- Application number: 12/983,547
- Filed: 2011-01-03
- Published: 2011-05-05
- Granted: 2015-04-21
- Earliest claimed: 2004-12-15
- Assignees: The University of North Carolina at Chapel Hill; University of Florida Research Foundation, Inc.
- Applicants: Dawn E. Bowles; Chengwen Li; Joseph E. Rabinowitz; Josh Grieger; Mavis Agbandje-McKenna; Richard Jude Samulski
- Inventors: Dawn E. Bowles; Chengwen Li; Joseph E. Rabinowitz; Josh Grieger; Mavis Agbandje-McKenna; Richard Jude Samulski
- Web page: https://patentgrep.com/patent/US9012224B2

## CPC

- C12N 15/86: Viral vectors
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 27/02: Ophthalmic agents
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 2750/14122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14144: Chimeric viral vector comprising heterologous viral elements for production of another viral vector
- 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

## Abstract

The present invention is based, in part, on the discovery that parvovirus (including AAV) capsids can be engineered to incorporate small, selective regions from other parvoviruses that confer desirable properties. The inventors have discovered that in some cases as little as a single amino acid insertion or substitution from a first parvovirus (e.g., an AAV) into the capsid structure of another parvovirus (e.g., an AAV) to create a chimeric parvovirus is sufficient to confer one or more of the desirable properties of the first parvovirus to the resulting chimeric parvovirus and/or to confer a property that is not exhibited by the first parvovirus or is present to a lesser extent.

## Claims

### Claim 1

A method of administering a nucleic acid to a cell comprising contacting the cell with a chimeric virus vector comprising:
a) a chimeric adeno-associated virus (AAV) capsid comprising a selective amino acid insertion immediately following amino acid position 264 in an AAV2 capsid subunit having the amino acid sequence of (SEQ ID NO:3) or a corresponding change in another AAV capsid subunit; and
b) a nucleic acid comprising an AAV terminal repeat sequence and a heterologous nucleic acid sequence,
wherein the nucleic acid is packaged within the chimeric AAV capsid.

### Claim 2

A method of delivering a nucleic acid to a subject comprising administering to the subject a chimeric virus vector comprising:
a) a chimeric adeno-associated virus (AAV) capsid comprising a selective amino acid insertion immediately following amino acid position 264 in an AAV2 capsid subunit having the amino acid sequence of (SEQ ID NO:3) or a corresponding change in another AAV capsid subunit; and
b) a nucleic acid comprising an AAV terminal repeat sequence and a heterologous nucleic acid sequence,
wherein the nucleic acid is packaged within the chimeric AAV capsid.

### Claim 3 (depends on 2)

The method of claim 2, wherein the subject is a human subject.

### Claim 4 (depends on 2)

The method of claim 2, wherein the subject has or is at risk for a disorder selected from the group consisting of a muscular dystrophy including Duchenne or Becker muscular dystrophy, hemophilia A, hemophilia B, multiple sclerosis, diabetes mellitus, Gaucher disease, Fabry disease, Pompe disease, cancer, arthritis, muscle wasting, heart disease including congenital heart failure or peripheral artery disease, intimal hyperplasia, a neurological disorder including epilepsy, Huntington's disease, Parkinson's disease or Alzheimer's disease, an autoimmune disease, cystic fibrosis, thalassemia, Hurler's disease, Krabbe's disease, phenylketonuria, Batten's disease, spinal cerebral ataxia, LDL receptor deficiency, hyperammonemia, anemia, arthritis, a retinal degenerative disorder including macular degeneration, adenosine deaminase deficiency, and cancer including tumor-forming cancers.

### Claim 5 (depends on 2)

The method of claim 2, wherein the chimeric virus vector or pharmaceutical formulation is administered to skeletal muscle.

### Claim 6 (depends on 5)

The method of claim 5, wherein the subject has or is at risk for muscular dystrophy.

### Claim 7 (depends on 5)

The method of claim 5, wherein the chimeric virus vector comprises a chimeric AAV capsid comprising a selective amino acid insertion following amino acid position 264 in an AAV2 capsid subunit.

### Claim 8 (depends on 5)

The method of claim 5, wherein the chimeric virus vector comprises a chimeric AAV capsid comprising a selective amino acid insertion following amino acid position 264 in an AAV3b capsid subunit.

### Claim 9 (depends on 2)

The method of claim 2, wherein the chimeric virus vector or pharmaceutical formulation is administered to cardiac muscle.

### Claim 10 (depends on 9)

The method of claim 9, wherein the subject has or is at risk for heart disease.

### Claim 11 (depends on 10)

The method of claim 10, wherein the subject has or is at risk for congestive heart failure or peripheral artery disease.

### Claim 12 (depends on 10)

The method of claim 10, wherein the chimeric virus vector comprises a chimeric AAV capsid comprising a selective amino acid insertion following amino acid position 264 in an AAV3b capsid subunit.

### Claim 13 (depends on 2)

The method of claim 2, wherein the chimeric virus vector or pharmaceutical formulation is administered to glial cells and/or astrocytes.

### Claim 14 (depends on 13)

The method of claim 13, wherein the subject has or is at risk for Parkinson's Disease, astrocytomas or glioblastoma.

### Claim 15 (depends on 13)

The method of claim 13, wherein the chimeric virus vector comprises a chimeric AAV capsid comprising a selective amino acid insertion following amino acid position 264 in an AAV2 capsid subunit.